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Vol. 82; n. 2, June 2010
Critical issues in chronic prostatitis.
Vittorio Magri, Gianpaolo Perletti, Riccardo Bartoletti, Tommaso Cai, Irina Emelyanova, Aare Mehik,
Giuseppe Morgia, Visnja Skerk, Alberto Trinchieri, Florian M.E. Wagenlehner, Kurt G. Naber
Paediatric urolithiasis in central coast region of Tunisia: Clinical characteristics.
Poste Italiane S.p.A. - Spedizione in abbonamento postale - D.L. 353/2003 (conv. in L. 27/02/2004 n. 46) Art. 1, comma 1 DCB Milano
Akram Alaya, Abdellatif Nouri, Mohamed Fadhel Najjar
Pyrrolidine dithiocarbamate treatment prevents ethylene glycol-induced urolithiasis
through inhibition of NF-kB and p38-MAPK signaling pathways in rat kidney.
Yusuf Özlem İlbey, Emin Özbek, Abdulmuttalip Şimşek, Mustafa Cekmen, Adnan Somay, Ali Ihsan Tasci
Prostate cancer detection after one or more negative extended needle biopsy:
Results of a multicenter case-findings protocol.
Pietro Pepe, Giuseppe Dibenedetto, Massimo Gulletta, Francesco Pietropaolo, Giancarlo Minaldi,
Venerando Gulino, Michele Barbera, Salvatore Rotondo, Guido Azzarello, Franco Amico, Francesco Aragona
Is it possible to predict post-residual voided urine by bladder scan before uroflowmetry
– a useful and timesaving test to reduce the number of non –
evaluable uroflow measurements?
Mauro Dicuio, Stepan Vesely, Tomas Knutson, Jan-Erik Damber,
Diego Ettore Cuzzocrea, Christer Dahlstrand
Sarcoma of prostate: Case report and review of the literature.
Gianna Pace, Roberto Pomante, Carlo Vicentini
Laparoscopic versus open radical retropubic prostatectomy:
A case-control study at a single institution.
Francesco Saverio Grossi, Sebastiano Di Lena, Donato Barnaba,
Lorenzo Larocca, Michele Raguso, Giovanni Sallustio, Nicola Raguso
Ureteral injury concomitant with kidney injury due to blunt trauma: Case report.
Murad G. Asali, Igor Romanowsky, Jacob Kaneti
Thirty years old man with a huge benign prostatic enlargement.
Pavlos Gkritsios, Asterios Fotas, Michael Bekas, Vasilis Adamou, Vasileios Katsikas
Metastasis to the renal hilum from malignant melanoma of the anterior trunk:
An unusual finding.
Francesco Pinto, Emanuele Cappa, Antonio Brescia, Emilio Sacco, Andrea Volpe,
Angelo Totaro, Mario Gardi, Francesco Pierconti, Pier Francesco Bassi
Interstitial cystitis with plasma cell bladder infiltration: Case report and literature review.
Mauro Pacella, Virginia Varca, Fabio Venzano, Carlo Toncini, Giorgio Carmignani, Alchiede Simonato
Lidocaine spray administration during transrectal ultrasound guided prostate biopsy
modified the discomfort and pain of the procedure:
Results of a randomized clinical trial.
Lucio Dell’Atti, Carlo Daniele
Extracorporeal shock wave therapy in the treatment of Peyronie’s disease:
Long term results.
Gian Maria Busetto
Official Journal of the SIEUN, the SIUrO, the UrOP
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SIEUN EDITORIAL BOARD
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UrOP EDITORIAL BOARD
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ASSOCIAZIONE UROLOGI LOMBARDI EDITOR
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HONORARY EDITOR
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Indexed in: Medline/Index Medicus - EMBASE/Excerpta Medica - Medbase/Current Opinion - SIIC Data Base
www.architurol.it
Contents
Critical issues in chronic prostatitis.
Pag. 75
Vittorio Magri, Gianpaolo Perletti, Riccardo Bartoletti, Tommaso Cai, Irina Emelyanova, Aare Mehik,
Giuseppe Morgia, Visnja Skerk, Alberto Trinchieri, Florian M.E. Wagenlehner, Kurt G. Naber
Paediatric urolithiasis in central coast region of Tunisia: Clinical characteristics.
Pag. 83
Akram Alaya, Abdellatif Nouri, Mohamed Fadhel Najjar
Pyrrolidine dithiocarbamate treatment prevents ethylene glycol-induced urolithiasis
through inhibition of NF-kB and p38-MAPK signaling pathways in rat kidney.
Pag. 87
Yusuf Özlem İlbey, Emin Özbek, Abdulmuttalip Şimşek, Mustafa Cekmen, Adnan Somay, Ali Ihsan Tasci
Prostate cancer detection after one or more negative extended needle biopsy:
Results of a multicenter case-findings protocol.
Pag. 95
Pietro Pepe, Giuseppe Dibenedetto, Massimo Gulletta, Francesco Pietropaolo, Giancarlo Minaldi,
Venerando Gulino, Michele Barbera, Salvatore Rotondo, Guido Azzarello, Franco Amico, Francesco Aragona
Is it possible to predict post-residual voided urine by bladder scan before uroflowmetry
– a useful and timesaving test to reduce the number of non – evaluable uroflow measurements?
Pag. 100
Mauro Dicuio, Stepan Vesely, Tomas Knutson, Jan-Erik Damber,
Diego Ettore Cuzzocrea, Christer Dahlstrand
Sarcoma of prostate: Case report and review of the literature.
Pag. 105
Gianna Pace, Roberto Pomante, Carlo Vicentini
Laparoscopic versus open radical retropubic prostatectomy:
A case-control study at a single institution.
Pag. 109
Francesco Saverio Grossi, Sebastiano Di Lena, Donato Barnaba,
Lorenzo Larocca, Michele Raguso, Giovanni Sallustio, Nicola Raguso
Ureteral injury concomitant with kidney injury due to blunt trauma: Case report.
Pag. 113
Murad G. Asali, Igor Romanowsky, Jacob Kaneti
Thirty years old man with a huge benign prostatic enlargement.
Pag. 116
Pavlos Gkritsios, Asterios Fotas, Michael Bekas, Vasilis Adamou, Vasileios Katsikas
Metastasis to the renal hilum from malignant melanoma of the anterior trunk:
An unusual finding.
Pag. 119
Francesco Pinto, Emanuele Cappa, Antonio Brescia, Emilio Sacco, Andrea Volpe,
Angelo Totaro, Mario Gardi, Francesco Pierconti, Pier Francesco Bassi
Interstitial cystitis with plasma cell bladder infiltration: Case report and literature review.
Pag. 122
Mauro Pacella, Virginia Varca, Fabio Venzano, Carlo Toncini, Giorgio Carmignani, Alchiede Simonato
Lidocaine spray administration during transrectal ultrasound guided prostate biopsy
modified the discomfort and pain of the procedure: Results of a randomized clinical trial.
Pag. 125
Lucio Dell’Atti, Carlo Daniele
Extracorporeal shock wave therapy in the treatment of Peyronie’s disease: Long term results.
Pag. 128
Gian Maria Busetto
ERRATA CORRIGE
The names of the Authors of the paper “Incidental urinary tract pathologies in the one-stop prostate cancer clinic” published in
Archivio Italiano di Urologia e Andrologia vol. 82 n. 1, March 2010 are as follows: Aza Mohammed, Iqbal S. Shergill,
Muhammad T. Vandal, Sandeep S. Gujral.
Archivio Italiano di Urologia e Andrologia 2010, 82, 2
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REVIEW
Critical issues in chronic prostatitis.
Vittorio Magri 1, Gianpaolo Perletti 2, Riccardo Bartoletti 3, Tommaso Cai 3,
Irina Emelyanova 4, Aare Mehik 5, Giuseppe Morgia 6, Visnja Skerk 7,
Alberto Trinchieri 8, Florian M.E. Wagenlehner 9, Kurt G. Naber 10
1 Urology
and Sonography Primary Care Clinic, Azienda Ospedaliera Istituti Clinici di Perfezionamento,
Milano, Italy;
2 Laboratory of Toxicology and Pharmacology, Department of Structural and Functional Biology, Università
degli Studi dell’Insubria, Busto A., Varese, Italy;
3 Department of Clinical Care, Medicine and Surgery, Urology Unit, University of Florence, and Division
of Urology, S. Maria Annunziata Hospital, Florence, Italy;
4 Department of Urology/Andrology, Medical Center “Rus”, Vladivostok, Russia;
5 Department of Surgery/Division of Urology, Oulu University Hospital, Oulu 90220 Finland;
6 Department of Urology, University of Messina, Messina, Italy;
7 Dr. Fran Mihaljeviç University Hospital for Infectious Diseases, Zagreb, Croatia;
8 Urology Complex Structure, A. Manzoni Hospital, Lecco, Italy;
9 Department of Urology, Pediatric Urology and Andrology, Justus-Liebig-University, Giessen, Germany;
10 Technical University Munich, München, Germany
Summary
In the last decade, an impressive amount of clinical research data has shed new light
on pathogenesis and management of the chronic prostatitis syndrome. A new classification and a validated symptom score have enabled urologists worldwide to speak a
“common language”, thus greatly improving the amount and quality of focused
research in this field. In Europe, a large number of groups and experts have been
actively involved in this research, and have developed in many cases a genuine view on prostatitis and chronic pelvic pain etiology, diagnosis and treatment. The present paper, written by a
panel of researchers from Europe and Far East Russia, reviews the most recent findings, discusses the most controversial contemporary topics on prostatitis syndromes, and highlights a
number of unresolved issues requiring further research and study.
KEY WORDS: Prostatitis; Chronic Bacterial Prostatitis; Chronic Pelvic Pain Syndrome; NIH-CPSI; P/CPPS.
Received 22 January 2009; 20 April 2009
INTRODUCTION
The chronic prostatitis (CP) syndrome includes a group
of diseases of bacterial and non-bacterial etiology, characterized by pelvic pain, voiding dysfunction and additional signs/symptoms (1).
The adoption of the NIH Chronic Prostatitis Symptom
Index (NIH-CPSI) as an internationally-acknowledged
symptom inventory, the use of low urinary tract segmented tests, the application of a novel classification system
(1) and the administration of fluoroquinolones as firstline agents were major landmarks in research and clinical
management of CP in the last decade. However, due to
the complexity and heterogeneity of this syndrome, the
knowledge about etiology, diagnosis and treatment of CP
is continuously revised and discussed (2).
Rather than reviewing basic concepts already described
in several comprehensive publications (3-7), this article
focuses on critical, debated issues regarding classification, diagnosis and treatment of CP. The discussion of
these topics is based on recently published evidence, on
research experience and on the “real-life” practice of a
panel of urologists and scientists from Europe and Far
East Russia, who attended an international prostatitis
meeting in the greater Milan Area in November 2008.
Critical issues were thoroughly discussed and are presented here. Practical examples concerning the various
diagnostic and therapeutic approaches to the various
subclasses of prostatitis, adopted by different European
groups are also provided.
CLASSIFICATION
OF
PROSTATITIS
The contemporary classification system for prostatitis
was approved by a NIH-NIDDK workshop committee in
1999 (8), and represents today’s standard for research:
Category I Acute Bacterial Prostatitis (ABP) is an acute
prostate bacterial infection, in patients showing local
Archivio Italiano di Urologia e Andrologia 2010; 82, 2
75
V. Magri, G. Perletti, R. Bartoletti, T. Cai, I. Emelyanova, A. Mehik, G. Morgia, V. Skerk, A. Trinchieri, F.M.E. Wagenlehner, K.G. Naber
(pain, voiding disturbances, pyuria, bacteriuria) and systemic (fever, malaise, etc.) signs/symptoms;
Category II Chronic Bacterial Prostatitis (CBP) occurs when
a patient undergoes recurrent episodes of urinary tract
infection (UTI) caused by an uropathogen, and if the
prostate is identified as the focus of these infections;
Category III Chronic Prostatitis/Chronic Pelvic Pain Syndrome
(CP/CPPS) is mostly defined by exclusion criteria, being
characterized by urological pain as major component.
Patients with the inflammatory “a” subtype of CP/CPPS
have leukocytes in their expressed prostatic secretions
(EPS), post-massage urine, or semen. Patients with the
noninflammatory “b” subtype have no apparent evidence
of inflammation.
In category IV Asymptomatic Inflammatory Prostatitis (AIP),
no subjective symptoms are shown by subjects usually
undergoing prostate biopsy or EPS analysis.
Chronic Bacterial Prostatitis
Category II CBP is traditionally characterized by recurrent episodes of UTI caused by acknowledged
uropathogens. Between symptomatic UTI episodes,
lower urinary tract (LUT) segmented cultures show an
infected prostate as the focus of these infections (8).
As a consequence, the diagnosis of category III CP/CPPS
is a diagnosis “of exclusion”, made in symptomatic
patients with “no demonstrable infection” of the prostate
(9, 1), corresponding to the former categories of “abacterial prostatitis” and “prostatodynia”. There is, however,
contoversy between experts on how to classify patients
with chronic prostatitis and pathogens localized to the
prostate, but lacking a history of recurrent UTIs.
Some experts classify these patients into category III
CP/CPPS by creating a new subcategory of “infectious/
bacterial CP/CPPS” as proposed in the context of the
recently published UPOINT phenotype classification
(10,11). The idea of this classification is that category III
CP/CPPS patients represent a very heterogenous group
with urinary, psychosocial, organ specific symptoms,
infection, neurologic symptoms and/or skeletal muscle
tenderness (UPOINT). The composition and severity of
these symptoms, however, vary widely between patients.
The authors hypothesize that if patients could be stratified
according to the composition of their symptoms and treated accordingly by a multimodal therapeutic approach, the
final clinical outcome should be more favourable.
This hypothesis looks quite attractive, but needs to be substantiated by appropriate clinical studies. It is, however,
not quite logical why a chronic infectious prostatitis caused
by classical uropathogens, e.g. E. coli, Enterobacteriaceae or
Enterococcus, with a history of recurrent symptomatic
UTIs, and a chronic infectious prostatitis caused by the
same classical uropathogens without a history of recurrent
UTIs should be classified into two different categories. So
far it is not known whether a difference can be found by
clinical studies comparing the outcomes of antibacterial
treatment in patients showing prostatic infection in the
presence or absence of a history of recurrent UTIs.
If a more specific phenotyping is the reason for proposing
the UPOINT system, then it would be more logical to differentiate between cat.II CBP on one side with subcategories according to the presence/absence of UTI history or
76
Archivio Italiano di Urologia e Andrologia 2010; 82, 2
to the type of pathogens, and cat.III CP/CPPS without an
infectious component on the other side. In both categories
patients could then also be phenotyped according to all
the other UPOINT symptoms. Alternatively, symptomatic
CBP and CP/CPPS patients could be lumped together and
phenotyped according to the six UPOINT categories.
The panel of speakers at the Milan meeting, authoring
the present article agreed that it is very important to
stratify patients into those with an infectious component
and those without demonstrable infection of the prostate.
Therefore, they rather propose to classify the group with
a chronic prostatic infection with and without a history
of recurrent UTIs into category II and those without an
infectious component into category III until more convincing arguments will be available. This does not represent a trivial diagnostic exercise, but is rather a key-issue,
bearing major therapeutic implications, such as the
optionality, the aggressiveness and the duration of antibacterial treatment and, ultimately, the success of therapy.
This does not mean that an exact diagnosis of an infectious component is always easy. The mere laboratory evidence of the presence or absence of bacteria is often not
sufficient to proof or exclude infection. Like in other
chronic infectious diseases the final diagnosis is established by clinical and specific laboratory investigations
and sometimes only by treatment outcome.
Chronic Prostatitis/Chronic Pelvic Pain Syndrome
A controversial issue in prostatitis classification is the
usefulness and appropriateness of dividing cat.III
CP/CPPS into inflammatory (“a”) and non-inflammatory
(“b”) subclasses on the basis of the clinical presentation
of patients, of the results of diagnostic tests and on the
outcome of therapeutic interventions.
Leukocytes detected in EPS, post-massage urine or semen
were considered markers of an inflammatory process
likely caused by an undetected infection and triggering an
immune response by lymphocytes, neutrophils,
macrophages. Thus, despite assignment to the IIIa subcategory, the empirical administration of antibacterial
agents was justified, as in cat.II CBP. However, the role of
such hypothetic infection was never substantiated nor
was a validated cutoff defined to differentiate between IIIa
and IIIb subclasses of CP/CPPS, which would probably
require different therapeutic approaches.
Non-inflammatory prostatitis, i.e. “an inflammatory condition without inflammation”, may indeed represent an odd
oxymoron. It is the opinion of the Milan panel that a “prostatitis without evidence of inflammation” most likely does
not represent a static situation, but is rather a quiescent
stage of a condition fluctuating between an active/productive phase, characterized by leukocytosis, and a
repair/organization phase with mucosal oedema regression,
increased blood circulation, decrease of infiltrating
immune cells and activation of tissue repair mechanisms,
accompanied by fibrosis and/or atrophy. Additionally, cellular signs of inflammation may not always be demonstrable, although inflammation may be present. Without new
evidence of nature and progression of inflammation in
CP/CPPS, the classification into IIIa or IIIb subclasses
should not be modified, although there is consensus
among the authors that the two subclasses widely overlap
Critical issues in chronic prostatitis
regarding signs, symptoms and response to therapy.
Moreover, there is extensive evidence that leukocyte counts
do not correlate with symptom severity in CPPS patients
(12). Although potentially useful for research purposes,
the subclassification into IIIa and IIIb may not be relevant
for routine clinical workup and therapeutic management.
If a differential outcome of a specific therapeutic intervention will be demonstrated in the future (e.g., a positive
response to antibacterial treatment in IIIa but not in IIIb),
this classification system may be further supported.
Moreover, studies are needed to conclusively demonstrate the absence of infiltrating inflammatory cells in the
prostatic tissue of patients with low or no leukocytes
counts in prostatic secretions.
ETIOLOGY
OF CHRONIC BACTERIAL PROSTATITIS
ROLE OF NON-TRADITIONAL UROPATHOGENS
-
Since its first consensus definition, CBP was acknowledged to be caused by “E. coli, other Gram-negative
organisms, or Enterococcus spp.” (8). However, the etiologic role of organisms other than these uropathogens
has been recurrently proposed and debated. Several scientists retain the original conviction that Enterobacteria,
Pseudomonas, Enterococci and few other genuses like
Staphylococcus aureus are the causative agents of CBP
(reviewed in: (1)). This is also based on studies reporting
inconsistent findings of Gram-positive species in
prostate-specific specimens (13).
Due to increasing evidence, other authors extend the
spectrum of prostatitis pathogens to organisms involved
in sexually-transmitted diseases, like Chlamydia trachomatis, Mycoplasmata and Trichomonas vaginalis (1418). On the basis of clinical experience and of the outcome of trials showing comparable clinical/symptomatic
response to antibacterial treatment, other researchers
add to the spectrum of potential causative pathogens
Gram-positive bacteria, like coagulase-negative Staphylococci, Streptococci, etc. (19, 20).
Although two recent studies from North America and
Europe demonstrated a strong correlation between eradication and clinical remission rates in patients showing
infection by either traditional uropathogens or nontraditional uropathogens (NTU) (21, 22), the issue is still controversial. Published data are still contradictory and further
investigation is required. Indeed, with the exception of
studies on C. trachomatis (14), reports describing the etiological hypothesis of NTU in CP have not focused on a single pathogen in a large patient population, but were based
on patients showing prostatic localization of bacteria very
different in terms of metabolic activity, virulence, and pathogenic potential. Placebo-controlled studies focusing on
single pathogens will shed new light on this issue.
DIAGNOSIS
OF
PROSTATITIS SYNDROMES
Diagnostic Workup
All panel members recommend some form of LUT segmented test in symptomatic patients, since the main purpose of the prostatitis diagnostic workup remains to ascertain whether patients suffer from a treatable infectious dis-
ease or not. The basic diagnostic procedures adopted by
the panel members include:
1. Detailed history;
2. Thorough urological/andrological visit with digital
rectal examination;
3. NIH-CPSI questionnaire;
4. Uroflowmetry with residual urine assessment;
5. Urethral swab;
6. 4-glass test according to Meares/Stamey or 2-glass
pre/post-massage test with culture and microscopy
(leukocyte counts);
7. Semen analysis and culture;
8. Serum PSA;
9. Transrectal ultrasound.
Additional exams, adopted by some of the authors in
their practice, include:
1. Additional questionnaires (IPSS, AMS, IIEF, CASXII, MSHQ);
2. Abdominal/pelvic ultrasound;
3. Hypoecoic periurethral zone volume measurement
(23);
4. Analysis of inflammatory markers (IL-2, IL-6, IL-8,
C-reactive protein) in serum or secretions;
5. Analysis of pathogen-specific IgAs in semen/secretions;
6. Analysis of Urinary Bladder Tumor Antigen;
7. Analysis of Sex hormone-binding globulin,
Testosterone, LH in serum;
8. 5-glass test, consisting of sequential Meares/Stamey
test followed by semen collection and analysis (24);
9. Intraprostatic Pressure Evaluation;
10. Cystoscopy;
11. Chlamydia, Herpesvirus, Cytomegalovirus, Hepatitis
B and C virus antibodies in serum;
12. Prostatic biopsy (in specific, recurrent cases).
Interestingly, almost all panel members never administer
the NIH-CPSI questionnaire alone in their routine diagnostic workup. The International Prostate Symptom Score
(IPSS), the Aging Male Symptom (AMS), the Loran-Segal
CAS XII (25) and the International Index of Erectile
Function (IIEF) questionnaires are often added to the NIHCPSI questionaire. This indicates that specialists need additional information to further phenotype the patients´
symptoms. Although the NIH-CPSI is unanimously seen as
mandatory, it may be perceived as a starting rather than an
arrival point in optimal prostatitis diagnostic management.
Moreover, additional drawbacks and needs must be
addressed for improvement of diagnostic workup:
1. Neuropathic pain patterns have not been sufficiently
studied, and should be further investigated.
2. There is poor correlation between prostatitis symptoms and biopsy findings; further investigation is
required.
3. Immune reaction in the prostate of CPPS patients is
not realistically measured; validated tests are needed.
4. Algorithms describing the evaluation and processing
of biopsies taken in prostatitis patients should be
elaborated.
5. Inflammatory markers other than white blood cells
need to be internationally validated.
Archivio Italiano di Urologia e Andrologia 2010; 82, 2
77
V. Magri, G. Perletti, R. Bartoletti, T. Cai, I. Emelyanova, A. Mehik, G. Morgia, V. Skerk, A. Trinchieri, F.M.E. Wagenlehner, K.G. Naber
Sexual dysfunction in prostatitis
Sexual dysfunction (SD) has a major impact on the quality of life of prostatitis patients (26-31). SD may be psychogenic or organic, or may be secondary to an inflammatory condition of the pelvic area. Clinical evidence
showing improvement of SD parallel to cure/remission
from CBP or CP/CPPS is lacking. The NIH-CPSI questionnaire does not address this major component of the prostatitis symptom array. Almost all authors routinely use
questionnaires (e.g., IIEF; MSHQ) related to SD in clinical
studies and in daily clinical practice. In some cases, questionnaires are also proposed to patients' sexual partners.
Because IIEF and MSHQ questionnaires address adequately all major issues related to sexual function, no new
diagnostic tools in this field are needed. However, these
questionnaires are not validated for prostatitis, and their
inner coherence should be confirmed in CP patients.
Additional diagnostic procedures for SD evaluation in CP
patients may include penile doppler sonography, Rigiscan,
local negative pressure diagnostics, lipid and hormone
profile. The response to phosphodiesterase-5 inhibitors
may also be used as a diagnostic tool for SD.
A detailed interview with the patient is extremely useful
in ascertaining the nature of the sexual disturbances and
in drawing a first psychosocial profile of the subject.
THERAPEUTIC OPTIONS
Tables 1 and 2 illustrate a variety of therapeutic options,
based on international guidelines (e.g., EAU guidelines), as
well as on the clinical experience and practice of the coauthors.
Acute Bacterial Prostatitis - Cat. I
For ABP, a “switch-therapy” programme may represent the
best therapeutic regime (Table 1). Initial empirical treatment with broad-spectrum parenteral antibacterial agents
(beta-lactams with or without aminoglycosides, fluoroquinolones, if local resistance levels are low) can be
switched to medium/long-term therapy with an oral fluoroquinolone, as soon as susceptibility testing is available
and acute symptoms (acute pain, retention, fever) subside.
Therapy may also include additional drugs like NSAIDS
and alpha-blockers, targeting pain, inflammation or
voiding disturbances (Table 1).
Chronic Bacterial Prostatitis - Cat. II
Oral fluoroquinolones, alone or combined with other
drugs, are first-choice agents, and should be administered for 4-6 weeks, if causative bacteria are susceptible
(Table 2). Antibacterial agents may be combined with
alpha-adrenoceptor blockers to treat voiding symptoms,
and to analgesic/anti-inflammatory agents. In some cases
therapy may include herbal extracts and other supplements that may show a tropism to the prostatic tissue
and may be beneficial in symptomatic relief.
Chronic Prostatitis/Chronic Pelvic pain Syndrome Cat. III
A large variety of therapeutic options are described in
Table 2 for therapy of CP/CPPS. This is probably due to
the fact that CP/CPPS is the most complex and difficult-
78
Archivio Italiano di Urologia e Andrologia 2010; 82, 2
to-treat condition among prostatitis syndromes, because
of the various clinical presentation patterns and of the
differential responsiveness of patients to treatment.
Category IIIa
Almost all panel members administer alpha-adrenoceptor blockers to cat.IIIa CP/CPPS patients, combined or
not with various drugs, herbal extracts and supplements.
Alpha-blocker therapy is usually long-term, and the
treatment regime should last at least 3-6 months.
The majority of the authors administer antibacterial agents
(fluoroquinolones, macrolides, co-trimoxazole, doxycycline) empirically as monotherapy or in combination with
other drugs, for a short time period. Antibacterial therapy
may be continued only in case of positive response.
Examples of drugs and other therapeutic interventions
for cat. IIIa CPPS are shown in Table 2.
Category IIIb
For therapy of cat.IIIb CP/CPPS, alpha-blockers may be
administered as in cat.IIIa. Herbal extracts and supplements (S.repens, P. africanum, Rye-grass pollen extract,
thioctic acid, sulbutiamine, vitamins) can also be administered. Empirical antibacterial agents are administered
less frequently than in cat.IIIa, and for shorter periods
(average: 2 weeks).
Examples of treatment strategies for category IIIb
CP/CPPS - additional or alternative to the ones listed for
cat.IIIa - are shown in Table 2.
Asymptomatic Inflammatory Prostatitis - Cat. IV
Due to its asymptomatic presentation, AIP is usually not
treated. Under certain circumstances, therapy to asymptomatic subjects is based on positive microbiological or
biochemical findings or elevation of serum PSA levels.
Short-term fluoroquinolones or co-trimoxazole may be
administered (average: 2 weeks), with or without antiinflammatory agents. In these cases, monitoring of PSA
levels and LUT segmented tests (to assess pathogen eradication) best follow the evolution of AIP.
Alpha-adrenoceptor blockers in CP
For many years, alpha-blockers have been included in
the toolbox of urologists, and have been recommended
for treatment of bacterial/abacterial prostatitis (5).
Recommendations were based on evidence that alphablockers relieve voiding symptoms and counteract/delay
exacerbation and infection relapses of chronic bacterial/abacterial prostatitis (32). Moreover, preclinical studies show that alpha-blockade may modulate neurogenic
inflammatory/irritative responses and nociceptive signals
in LUTs (33, 34), thus pointing to a pharmacological
activity of alpha-blockers beyond their mere urodynamic effects. Alpha-blockers were shown to be beneficial
either in randomized, placebo-controlled trials (35,36),
or in open-label studies performed in “real-life” clinical
settings (37). However, in 2004 the use of alpha-blockers in non-naive subjects has been discouraged by results
of a NIH-CPCRN trial showing that 6-week tamsulosin
versus placebo provided no additional bene?t in heavily
pre-treated CP/CPPS patients (38). A second NIHCPCRN randomized trial showed no benefit of alfuzosin
Critical issues in chronic prostatitis
Table 1.
Therapy of acute and chronic bacterial prostatitis.
Archivio Italiano di Urologia e Andrologia 2010; 82, 2
79
V. Magri, G. Perletti, R. Bartoletti, T. Cai, I. Emelyanova, A. Mehik, G. Morgia, V. Skerk, A. Trinchieri, F.M.E. Wagenlehner, K.G. Naber
Table 2.
Treatment of category III - chronic prostatitis/chronic pelvic pain syndrome.
compared to placebo also in drug-naive patients (39).
A possible explanation of the different results of the NIHCPCRN studies vs. the Mehik trial can be found in the different length of the treatment course with alpha-blockers
(CPCRN studies: 6-weeks (38) or 3 months (39); Mehik
study (35): 6 months). Indeed, the discrepancies between
these studies are probably apparent, because also in the
Mehik study no short-term difference was observed
between alfuzosin and placebo after 8 weeks of treatment.
However, the difference became significant at week 16.
In this respect, the authors of the CPCRN studies admit
that alfuzosin might have been beneficial in longer-term
treatment or if patients had shown more clinically significant voiding symptoms (39). Based on published evidence
and personal experience the Milan panel members agreed
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Archivio Italiano di Urologia e Andrologia 2010; 82, 2
that long-term alpha-blockers may be beneficial in symptom relief/remission in CBP and CP/CPPS patients. These
drugs should especially be administered in CP/CPPS
patients showing or claiming voiding disturbances.
RESEARCH PRIORITIES
AND
ONGOING INVESTIGATIONS
New frontiers and research priorities
The transition from the traditional spectrum of research
themes concerning CBP and CP/CPPS towards new biopsycho-social approaches, to identify and modulate maladaptive, cognitive and behavioral responses to pain is
interesting (40).
Because a perturbed psychological profile – causative or
Critical issues in chronic prostatitis
secondary to their condition – is frequently shown by
CP/CPPS patients, cognitive/behavioral interventions can
positively influence symptom perception through control
of pain and internal tension.
Additional research priorities include:
1. the genesis of pain in CP/CPPS patients, with emphasis on a possible neuropathic component of this symptom;
2. the causative role of Herpes simplex virus in prostatitis or in other pelvic conditions;
3. new strategies targeting skin reflexogenic zones,
responsible for the harmonic work of small pelvis
organs, including the prostate;
4. new tools (questionnaires?) to evaluate the subjective influence on pain perception and personal reactivity to pain;
5. the mechanisms causing rapid worsening of
pelvic/prostatic health after age 40 in men;
6. the relationship between atypical small acinar proliferation and prostate cancer;
7. the mechanisms of action of antioxidants like the
thioctic salt of alpha-lipoic acid;
8. the role of immune reaction in prostatic inflammation;
9. new diagnostic tests for classifying CP/CPPS, given
the limited accuracy of the Meares/Stamey or 2-glass
procedures;
10. new prostatitis preclinical models.
Ongoing investigations
A number of research projects on CBP and CP/CPPS are
performed in the authors’ institutions, in Europe and in
Far-East Russia, both at basic science and clinical levels.
Both etiology and therapy are investigated, with prevalence of the pathogenic determinants of CP/CPPS:
1. a multinational European epidemiological prevalence survey on CP/CPPS, 2008-2009,
2. influence of patient lifestyle on manifestation of
CP/CPPS,
3. role of atypical microorganisms in CBP,
4. role of Chlamydia trachomatis in CP/CPPS,
5. PK/PD, optimal dosage and duration of fluoroquinolone therapy, and other antibacterial regimens in CBP,
6. role and effect of antibacterial therapy in CP/CPPS,
7. new multimodal therapeutic algorithms in CP/CPPS,
8. relationship between prostatitis and cancer onset,
9. microbiological characterization of prostatic secretions and biopsies in the inflammatory reaction to
pathogens
10. hormonal influence on triggering inflammation of
the prostate and on the intensity of clinical symptoms in CP/CPPS,
11. relationship between histological and EPS/VB3
detection of white blood cells in CP/CPPS,
12. optimization of prostatitis therapy and drug safety profile by pharmacogenetic/pharmacogenomic testing,
13. application of Extracting microarray gene expression
Patterns and Identifying co-expressed Genes to
CP/CPPS research,
14. analysis of prostate tissue hypoxia levels,
15. new diagnostic markers related to prostatic tissue
immunity disturbances,
16. activity of 5-phosphodiesterase agents on pain and
sexual disturbances in CP/CPPS,
17. efficacy and tolerability of treatment with Serenoa
repens, lycopene and selenium in cat. IIIb CP/CPPS,
18. role and significance of calcifications in prostatitis
syndromes,
19. new diagnositic procedures for CP/CPPS
CONCLUSIONS
In the last decade, impressive amounts of clinical and
preclinical research data have shed light on the pathogenesis and management of chronic prostatitis syndromes. NIH-sponsored programs in North America as
well as independent research worldwide have opened the
path to research in this field. A number of European
groups have been actively involved in this research effort,
and have in many cases developed an original view on
prostatitis and chronic pelvic pain. The variety of diagnostic and therapeutic options summarized in this paper,
and the number of ongoing studies presented herewith,
demonstrate the richness and originality of European
and Eurasian research, and may open new possibilities of
international collaborative interactions.
ACKNOWLEDGEMENTS
“We thank KONPHARMA for sponsoring the November
2008 meeting, whose outcomes inspired the preparation
of the present article”.
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Correspondence
Magri Vittorio, MD; Urology and Sonography Primary Care Clinic
Azienda Ospedaliera Istituti Clinici di Perfezionamento, Milano, Italy
[email protected]
Gianpaolo Perletti, MD; Università degli Studi dell’Insubria,
Laboratory of Toxicology and Pharmacology,
Via A. Da Giussano, 12 - 21052 Busto A., Italy. [email protected]
Bartoletti Riccardo, MD; Cai Tommaso, MD; Department of Clinical
Care, Medicine and Surgery, Urology Unit, University of Florence,
and Division of Urology, S. Maria Annunziata Hospital, Florence, Italy
Emelyanova Irina, MD; Department of Urology/Andrology,
Medical Center "Rus", Vladivostok, Russia
Mehik Aare, MD, PhD; Department of Surgery Division of Urology
Oulu University Hospital, Finland
Morgia Giuseppe, MD; Department of Urology, University of Messina
Messina, Italy
Skerk Visnja, MD; Dr. Fran Mihaljević University Hospital for
Infectious Diseases, Zagreb, Croatia
Trinchieri Alberto, MD; Urology Unit - Ospedale A. Manzoni
23900 Lecco, Italy
Wagenlehner Florian ME, MD; Department of Urology, Pediatric
Urology and Andrology, Justus-Liebig-University, Giessen, Germany
Naber Kurt G, MD; Technical University Munich,
München, German
ORIGINAL PAPERS
Paediatric urolithiasis in central coast region
of Tunisia: Clinical characteristics.
Akram Alaya 1, Abdellatif Nouri 2, Mohamed Fadhel Najjar 1
1 University
2 University
Summary
Hospital, Department of Biochemistry and Toxicology, 5000 Monastir, Tunisia;
Hospital, Department of Pediatric Surgery, 5000 Monastir, Tunisia
Objective: To show an outline of the clinical and biological characteristics of paediatric
urolithiasis among Tunisian children in the coast region.
Patients and methods: This retrospective study included 168 children under the age of
16 years presented with urinary stones (100 boys and 68 girls). Patients were
reviewed in a multi-centric study with regard to age at diagnosis, sex, history, and
physical, laboratory, and radiologic findings. The physical and chemical analysis of stones was
carried out respectively by a stereomicroscope and by infra-red spectroscopy.
Results: The sex ratio was 1.47. The clinical presentation of this pathology was dominated by
abdominal pain (28%), hematuria (25.6%), dysuria (16.7%) and urinary tract infection
(14.3%). Stones were located in the upper urinary tract in 75.6% of cases. Of the urine cultures,
14.3% were positive. Whewellite was more frequent in children stones than in infants (p < 0.05)
and was the main component in 46.4% of stone section and 55.4% in stone surface.
Conclusion: The male prevalence of paediatric urolithiasis is progressively decreasing in
Tunisia. The epidemiological profile of renal stones in our country has changed towards a predominance of calcium oxalate stone and upper tract location.
KEY WORDS: Stone; Children; Infrared spectroscopy; Tunisia.
Submitted 30 November 2008; Accepted 15 January 2009
INTRODUCTION
Urolithiasis in children is a frequent disease characterized by its varied pathophysiological background (1).
Clinical investigations of a patient with urolithiasis
include a careful history, radiological and biochemical
evaluation. It’s always important to define the cause of
urinary calculi disease among children to prevent reccurence and possible impairing of renal function (2). A
number of publications have previously reported the
high prevalence and particular patterns of stone disease
among children in developing countries (2).
Our study is interested in the urolithiasis of the child in
the area of the Tunisian Coast. By confronting the clinical data and the results from the stone analysis, we present an outline on the current state of the renal lithiasis of
the child on the coast of Tunisia.
PATIENTS
AND METHODS
Between June 1996 and February 2008, 168 children (68
females, 100 males; mean age 7.3 years; age range 0.25-16
years) suffering from urinary calculi and evaluated in our
department were enrolled in the study. In each case age
and sex of the patient, stone location, and circumstances
of discovery were recorded. Various biochemical parameters indicative of renal functional status (serum calcium,
phosphorus, alkaline phosphatase, creatinine, uric acid
and electrolyte levels) were evaluated in 126 cases.
Stone analysis: the structure of each calculus was established using stereomicroscope to define the morphology
of the stone and to select its representative parts (nucleus or core, internal section, and external surface), in
order to determine its molecular and crystalline composition by infrared spectroscopy. From 0.5 to 2 mg of
powder, of each stone part, was pulverised within an
inert powdered support (dried potassium bromide) in a
proportion of 0.5 to 2% in an agate mortar. This mixture
was transferred into an appropriate die and pressed at
10t/cm2 to form a transparent pellet 13 mm in diameter.
The spectral region investigated was from 4000 to 400
cm-1. Reference spectra were pure potassium bromide
(KBr) pellets. Spectra were recorded by means of a
Bruker IFS25 Fourier transform infrared spectrometer.
Archivio Italiano di Urologia e Andrologia 2010; 82, 2
83
A. Alaya, A. Nouri, M. Fadhel Najjar
The various compounds were identified by comparison
with previously published reference spectra. The results
were expressed according to the main crystalline phase
found in the stones and named as follows: whewellite
(calcium oxalate monohydrate), weddellite (calcium
oxalate dihydrate), carbapatite (carbonated calcium
phosphate crystallized in the hexagonal system), struvite
(magnesium ammonium phosphate hexahydrate), and
calcite (anhydrous calcium carbonate). The stone component was considered as main component if it exceeded 70% of the total composition of calculus.
Statistical analysis of these data was carried out using
software SPSS 11.0 for Windows.
RESULTS
Children were aged between 3 months and 16 years (mean
age 7.3 years). 15.47% of the cases were infants, aged
between 3 months and 2 years. Urolithiasis was more frequent among boys. The sex ratio was 1.47 (100 boys and
68 girls). This ratio was 2.71 among infant patients. The
most frequent initial symptoms were abdominal pain
(28.0%) (Table 1), which was prevalent in school age children (30.3% in children vs 15.4% in infants) (p < 0.05),
hematuria in 25.6% of cases and dysuria in 16.7%. Infants
seem to be most frequently affected by urinary tract infection than children (26.9% vs 12.0%) (p < 0.05). A family
history of urolithiasis was recorded for 19 patients (8.9%).
Thirteen patients (7.7%) had an underlying anatomic
abnormality, including vesicoureteral reflux in 4 cases,
uretero-pelvic junction obstruction in 8 cases and valves
of the posterior urethra in one case. Urinary calculi were
more frequently located in the upper urinary tract
(75.6%) than in the lower urinary tract (Figure 1).
Bladder stones were more frequent in boys than girls
(29.0% vs 7.4%) (p < 0.05). Multiple stones were found
in 108 patients (64.2 %).
Evaluation of metabolic risk factors in 24-h urine samples revealed 22 children (13.1%) with a single risk factor, among which hyperoxaluria (3 cases), hypercalciuria
(11 cases), cystinuria (2 cases) and hypocitraturia (6
cases) seemed to be the commonest. Among the possible
predisposing factors, 24 patients (14.3%) had urinary
tract infection (UTI) at the time of diagnosis and were
treated with appropriate medication. The bacteria isolated were Proteus in 12 cases, Escherichia coli in 8,
Klebsiella pneumoniae in 2, and Streptococcus and
Staphylococcus aureus in 1 case each. 167 children were
treated by open surgery and one by endoscopy.
The stone composition was homogeneous (> 90-95% of
stone composition) in 37.5% of cases and calcium
oxalate represented the more common component
(60.0%). Purine stones were pure in 24.6% of cases.
As shown in table 2, the main component of the urinary
stones – determined by infrared spectroscopy – was
whewellite in 89 cases (53.3%). Struvite stones were
associated with urinary tract infection in 66.6% of cases.
The nucleus of stone was examined (found) in 6 cases
(3.5%). The main component of the nucleus was ammonium urate in 33.3% of cases.
Table 1.
Clinical presentation of Tunisian children with urolithiasis according to age.
Clinical presentation
Abdominal pain
Hematuria
Dysuria
Urinary tract nfection
Colic
Anuria
Fever
Accidental finding
Infants
Number
%
4
15.4
9
34.6
1
3.8
7
26.9
0
0
3
11.5
2
7.7
0
0
Table 2.
Main* stone composition.
Main stone component
Whewellite
Ammonium urate
Carbapatite
Weddellite
Struvite
Uric acid anhydrous
Cystine
Total
Total
Number
%
89
53.3
23
13.8
18
10.2
16
9.6
13
7.8
7
4.2
2
1.2
168
100
*Present in more than 70% of the total stone composition.
84
Archivio Italiano di Urologia e Andrologia 2010; 82, 2
Children
Number
%
43
30.3
34
23.9
27
19
17
12
11
7.7
4
2.8
4
2.8
2
1.4
p
p
p
p
p
< 0.05
NS
< 0.05
< 0.05
NS
< 0.05
NS
NS
TOTAL
Number
%
47
28
43
25.6
28
16.7
24
14.3
11
6,5
7
4.2
6
3.6
2
1.2
Staghorn stones were noted in 14 cases. Their composition was dominated by whewellite (53.8%), struvite and
carbapatite (38.5% each).
DISCUSSION
The epidemiological data related to the North African
pediatric urolithiasis are very heterogeneous and not easily comparable to those observed in industrialised countries (2, 3).
The well-known male preponderance has been confirmed in our study, however this predominance is progressively decreasing compared to results previously
published since the end of sixties (4, 5). According to
some publications urolithiasis mainly affects babies (age
Paediatric urolithiasis in central coast region of Tunisia: Clinical characteristics
Figure 1.
Stone location.
Figure 2.
Main stone section and surface component.
< 2 years) than children (6-8). In Tunisia, the baby
urolithiasis was reported for the first time by Nahlovsky
in the area of Sousse (4), where a frequency of 31.4%
was recorded. Ten years later, in the same area, Najjar et
al. (5) reported a frequency of 37.8%. During the past 25
years, this frequency changed in the central coast of
Tunisia and it currently accounts for 15.47%.
Several studies noted a strong association between
urolithiasis and urinary tract infections (6, 9) although
it is not always easy to determine if the infection is the
cause or the consequence of lithiasis. The frequency of
the urinary tract infections was about 15 to 57% of the
lithiasic patients in the years 1970-1980 (6, 10) and
does not exceed at present in Europe the 2% (10). In
our series, infection characterised 14.3% of cases comparable with that found in North America (8%) (11).
This result was lower than that observed in England
(30%) (12), in Kuwait (29%) (13) and in the Northern
region of Tunisia (30%) (10), but it shows a decrease of
the infection rate with regard to our first study in 1986
where we found a 57% of cases (5). The rate of meta-
bolic abnormalities in our series (13.1%) is lower than
that detected in Kuwait (13) where it reached 83% of the
cases: this can be explained by the low level of biological
investigation in our study or by the high level of consanguinity in Kuwait.
In Europe, urinary stones are mainly located in the upper
urinary tract, and the proportion of bladder calculi does
not exceed 14% (6, 14). It is even absent in other industrialised countries such as the United States of America
(15). Bladder stones were only observed in the rural areas
of the developing countries (51.1% in Morocco (16) and
71% in Cameroon (1), however, in our series, they were
found in only 20.2% of cases (Najjar et al. 36.4%) (5),
(Kamoun et al. 24%) (2).
Calcium oxalate is the most frequent chemical compound in the urolithiasis; it is present
in approximately 80% of stones and
represents the majority component in
70% of them (17). These data agree
with our results that show that calcium
oxalate was the main component in 105
cases (62.5%). It was present in 54.7%
of the stone sections and 70.2% of the
surfaces. These values were lower than
those described in Pakistan (surface
85%, section 90%) (18) but comparable
with those observed in Morocco (19), in
Cameroon (1), and in our precedents
studies (20, 21). In our study we
observed a considerable modification of
the stone composition of Tunisian children since the Seventies, where uric
stone represented 83% (4). These
results confirm those observed by
Daudon et al. (22) which place the current profile of the paediatric urolithiasis
in Tunisia between the developing countries and the industrialized ones.
Calcium oxalate monohydrate (whewellite) remains the most frequent component in Tunisian children and infants
stones (20, 21, 23) even if its frequency was slightly
decreased during the last 12 years period (20). In our
study, whewellite was the main component in 53.3% of
stones, and its frequency was higher on the level of the
stone surface.
The presence of ammonium urate is especially considered
as a marker of endemic urolithiasis when it is pure or
associated with calcium oxalate and it constitutes the core
of stones (16). It is particularly rare in the industrialized
countries where it reaches 4.7% in France (24) whereas it
is relatively frequent in childhood stones from the developing countries of Africa such as Cameroon where it
reaches 57.1% (1). The ammonium urate was the main
component in only 13.8 % of cases, and in 19% of the
stones sections in our series. According to our results,
purines (ammonium urate + uric acid anhydrous) stones
were more frequent in infants than children. Metabolic
(genetic or acquired) disorders can be mentioned to
explain this change. However, we believe that tubular
immaturity in infants associated to a lack of reabsorption
of uric acid is the main reason in this case (16).
Archivio Italiano di Urologia e Andrologia 2010; 82, 2
85
A. Alaya, A. Nouri, M. Fadhel Najjar
Struvite remains the best marker of urinary tract infections
by urease producing bacteria (6, 10); 54% of struvite-containing stones are associated with a clinical infection (24).
These stones, can in some cases reach a considerable burden in the excretory cavities of the kidney, from that the
name of coralliform or staghorn stones. The frequency of
staghorn stones varies from 19 to 54% in childhood
urolithiasis (25); we found a 8.3% rate and an association
to urinary tract infections in 38.5% of cases. The presence
of whewellite in 53.8% of staghorn stones, is similar to the
results described by several authors who found an associated primary metabolic cause, mainly hypercalciuria (26),
which was not confirmed by our analyses.
In children with renal calculi, the aim of management
should be complete clearance of stones, preservation of
renal function and prevention of recurrence. In 167
cases, stone removal was achieved by open surgery. Our
opinion is that open surgical procedures still provide an
opportunity to clear stones in complex situations. In our
country, open surgery still remains an important option
due to the prevalence of large stones and calculi, and
basically to the scarcity of equipment for lithotripsy and
endourology in most paediatric surgical units (23).
18. Rizvi SA, Naqvi SA, Hussain Z, et al. Renal stones in children in
Pakistan. Br J Urol 1985; 57:618-621.
CONCLUSION
19. Bennani S, Debbagh A, Oussama A, et al. Spectrophotométrie
infrarouge et lithiase urinaire. À propos de 80 cas. Ann Urol 2000;
34:376-383.
The male prevalence of paediatric urolithiasis is progressively decreasing in Tunisia. The epidemiological profile
of renal stones in our country has changed towards a
predominance of calcium oxalate stone and upper tract
location. The increase of calcium oxalate stones in school
age children and the decrease of struvite and purines
stones confirm the change on the aetiology of urolithiasis according to age. The persistence of urate stones
reflects particular eating habits and infectious risk factors
specific of the rural population.
REFERENCES
1. Angwafo FF, Daudon M, Wonkam A, et al. Pediatric urolithiasis in
sub-saharian Africa: A comparative study in two regions of
Cameroon. Eur Urol 2000; 37:106-111.
2. Kamoun A, Daudon M, Abdelmoula J, et al. Urolithiasis in Tunisian
children: a study of 120 cases based on stone composition. Pediatr
Nephrol 1999; 13:920-925.
9. Kamoun A, Daudon M, Kabaar N, et al. Facteurs étiologiques de
la lithiase urinaire de l’enfant en Tunisie. Prog Urol 1995; 5:942-945.
10. Jungers P, Rieu P, Méria P, et al. Lithiase d’infection.
L’Eurobiologiste 2001; 254:23-28.
11. Sternberg K, Greenfield SP, Williot P, et al. Pediatric stone disease:
An evolving experience. J Urol 2005; 174:1711-1714.
12. Coward RJM, Peters CJ, Duffy PG, et al. Epidemioloy of paediatric renal stone disease in the UK. Arch Dis Child 2003; 88:962-965.
13. Al-Aisa AA, Al-Hunayyan A, Gupta R. Pediatric urolithiasis in
Kuwait. Int Urol Nephrol 2002; 33:3-6.
14. Daudon M, Jungers P. Epidémiologie de la lithiase urinaire.
L’Eurobiologiste 2001; 253:5-15.
15. Stapleton FB. Childhood stones. Endocrinol Metab Clin N Am
2002; 31:1001-1005.
16. Oussama A, Kzaiber F, Mernari B, et al. Analyse de la lithiase de
l’enfant dans le moyen Atlas Marocain par spectrométrie infrarouge.
Ann Urol 2000; 34:384-390.
17. Daudon M. Comment analyser un calcul et comment interpréter
le résultat. L’Eurobiologiste 1993; 203:35-46.
20. Alaya A, Nouri A, Najjar MF. Paediatric renal stone disease in
Tunisia: A 12 years experience. Arch Ital Urol Androl 2008; 80:50-55.
21. Alaya A, Belgith M, Jouini R, et al. La lithiase urinaire de l’enfant
en Tunisie. Aspects actuels à propos de 104 cas. Prog Urol 2006;
16:474-480.
22. Daudon M, Bounxouei B, Santa Cruz F, et al. Composition des calculs observés aujourd’hui dans les pays non industrialisés. Prog Urol
2004; 14:1151-1161.
23. Jallouli M, Jouini R, Sayed S, et al. Pediatric urolithiasis in
Tunisia: A multi-centric study of 525 patients. J.Pediatr Urol 2006;
2:551-554.
24. Daudon M. L’analyse morphoconstitutionnelle des calculs dans
le diagnostic étiologique d’une lithiase urinaire de l’enfant. Arch
Pédiatr 2000; 7:855-865.
25. Benchekroun A, Lachkar A, Iken A, et al. La lithiase coralliforme. À propos de 98 cas. Ann Urol 2000; 34:370-375.
26. Faure G, Sarramon JP. Discussion du rapport «La lithiase coralliforme». J Urol 1982; 88:671-677.
3. Pietrow PK, Pope JC, Adams MC, et al. Clinical outcome of pediatric stone disease. J Urol 2002; 167:670-673.
4. Nahlovsky J, Farhat M, Gharbi S. Fréquence extraordinaire de la
lithiase chez les enfants en Tunisie et leurs causes probables. J Urol
Nephrol 1969; 75:539-541.
5. Najjar MF, Najjar F, Boukef K, et al. La lithiase infantile dans la
région de Monastir étude clinique et biologique. Le Biologiste 1986;
165:31-39.
6. Jungers P, Daudon M, Conort P. Lithiase rénale, diagnostic et traitement. Paris: Flammarion Médecine-Sciences, 1999.
7. Ali SH, Rifat UN. Etiological and clinical patterns of childhood
urolithiasis in Iraq. Pediatr Nephrol 2005; 20:1453-1457.
8. Van Kote G, Lottmann H, Fremond B, et al. Lithotritie urinaire de
l’enfant. Etude multicentrique du Groupe d’Etudes en Urologie
Pédiatrique (GEUP). Ann Urol 1999; 33:308-314.
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Archivio Italiano di Urologia e Andrologia 2010; 82, 2
Correspondence
Akram Alaya
Department of Biochemistry and Toxicology
University Hospital, 5000 Monastir, Tunisia
[email protected]
Abdellatif Nouri
Department of Pediatric Surgery
University Hospital, 5000 Monastir, Tunisia
[email protected]
Mohamed Fadhel Najjar
Department of Biochemistry and Toxicology
University Hospital, 5000 Monastir, Tunisia
[email protected]
ORIGINAL PAPER
Pyrrolidine dithiocarbamate treatment prevents
ethylene glycol-induced urolithiasis through
inhibition of NF-kB and p38-MAPK signaling
pathways in rat kidney.
Yusuf Özlem İlbey 1, Emin Özbek 1, Abdulmuttalip Şimşek 1, Mustafa Cekmen 2,
Adnan Somay 3, Ali Ihsan Tasci 4
Bezm-i Alem Valide Sultan Vakif Gureba Research and Education Hospital, Department of Urology 1
and Pathology 3, Kocaeli University Department of Biochemistry 2,
Bakırköy Research and Education Hospital 4, Istanbul, Turkey
Summary
The aim of this study was to evaluate the role of the inducible nitric oxide synthase
(iNOS), selective nuclear factor-kB (NF-kB) and p38-mitogene-activated protein kinase
(p38-MAPK) on oxalate-induced crystal deposition in renal tubules. The rats were
divided into three groups; group 1; control group, group 2; ethylene glycol (EG) group,
group 3; EG + pyrrolidine dithiocarbamate (PDTC) group. Rats were sacrified on 7, 15
and 45th days. The iNOS expression, p65/NF-kB and p38/MAPK activity, and oxidative stress
markers were evaluated in the kidney. Crystal depositions were evident on day 7, mild and severe
cyrystallization were observed on day 15 and 45 in EG group, respectively. There was limited or
no cyrstal formation in the EG + PDTC group. While EG stimulates iNOS, p65/NF-kB and
p38/MAPK activity in renal tubules, PDTC inhibited it. PDTC prevents crystal depositions in
renal tubules by reducing oxidative stress, iNOS, NF-kB, and p38-MAPK expression.
KEY WORDS: Pyrrolidine dithiocarbamate; Inducible nitric oxide synthatase (iNOS); Nuclear factor kappa
B (NF-kB); p38-MAPK (mitogene–activated protein kinase); Lipid peroxidation; Oxidative stress; Calcium
oxalate crystals
Received 22 January 2009; Accepted 20 April 2009
INTRODUCTION
Stone formation in the kidney is one of the oldest and
most wide spread diseases known to man. Calcium-containing stones, especially calcium oxalate monohydrate,
calcium oxalate dihydrate and basic calcium phosphate
are the most commonly occuring ones to an extent of 7590% (1). Oxalate, a common constituent of kidney stones,
is normally excreted by the kidney. Hyperoxaluric states
including primary oxalosis and secondary hyperoxaluria
can lead to renal tubulointerstitial damage. Hyperoxaluria
is one of the major risk factors in human idiopathic calcium oxalate (CaOx) stone disease, and ethylene glycol (EG)
can be used to produce CaOx urolithiasis in rats (2).
Convincing evidence indicates that both oxalate and
CaOx crystals are harmful to renal epithelial cells and
induces lipid peroxidation by unknown mechanism
which causes disruption of the structural integrity of the
membranes in vivo as well as in cell cultures (3-5).
Reactive oxygen species (ROS) such as superoxide radi-
cals, hydroxyl free radicals and hydrogen peroxide act as
mediators of nuclear factor kapa-B (NF-kB) activation (6).
NF-kB is one of the ubiquitos transcriptional factor of
the inducible expression of many genes, including iNOS,
that encode proteins involved in the modulation of
inflammatory and host defense process (7). NF-kB family includes p50, p52, RelA (p65), Rel B, c-Rel, v-Rel and
dorsal and Dif proteins (8). Normally these are
squestered in the cytoplasm of cells through its binding
with its inhibitors, p 105 and inhibitor kappa B (I-kB)like proteins (8). Activation of NF-kB by external stimuli
such as cytokins or ROS causes the degradation of its
inhibitor Ik-B-alpha or proteolytic cleavage of p105. Free
NF-kB dimers translocates to nucleus and activates the
target genes, such as iNOS (9-11).
Mitogen-activated protein kinases (MAPK) are important
mediators involved in the intracellular network of interaction proteins that transduce extracellular stimuli to intraArchivio Italiano di Urologia e Andrologia 2010; 82, 2
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Özlem İlbey, E. Özbek, A. Şimşek, M. Cekmen, A. Somay, A.I. Tasci
cellular responses (12). Three distinct MAPK pathways
have been described; extracellular signal-regulated kinase,
c-Jun-N-terminal kinase, and p38-MAPK (13). p38MAPK is a ubiquitous, highly conserved protein kinase
that plays an important role in the inflammatory response
and in the apoptosis process (14, 15). p38-MAPK is activated by cytokines and cellular stress, and its activation
results in increased production of inflammatory cytokine
genes including interleukin-1β and tumor necrosis factorα (TNF- α) (15, 16). It has also been reported that p38MAPK may be involved in NF-kB activation (17).
Nitric oxide (NO) acts as an intercellular messenger and
regulates cellular functions such as vasorelaxation and
inflammation. NO has an important role in the elimination of pathogens and tumor cells; however, overproduced NO is oxidized to ROS and result in the disruption of cell signaling and uncontrolled systemic inflammation (18, 19).
Pyrrolidine dithiocarbamate (PDTC) is an antioxidant.
Recent studies have suggested that the pro-oxidant and
metal-chelating properties of PDTC could also be
involved in its ability to inhibit NF-kB (20-22). Some
studies showed that PDTC may inhibit NF-kB activation
via stabilization of the IkB-α (23), or likely via inhibition
of the ubiquitin-proteasome pathway (24). There are a
lots of studies concerning the selective NF-kB inhibitor
properties of PDTC (25).
The aim of this study was to evaluate the role of iNOS
expression, and p38-MAPK and NF-kB systems activation in the pathogenesis of EG-induced urolithiasis, and
to investigate the possible inhibitory effects of PDTC
known as a selective NF-kB inhibitor against the stone
formation.
MATERIALS
AND METHODS
Animals
In this study, 54 healthy, male Spraque-Dawley rats (240250 g) were used. The animals were kept under standard
laboratory conditions (12 hours lightness, 12 hours
darkness, 26-28°C) for at least one week before the
experiment and those conditions were preserved till the
end of the experiment. Animal cages were kept clean,
feed and water were given regularly every day. All experiments in this study were performed in accordance with
the guidelines for animal research from the National
Institutes of Health and were approved by the Local
Committee on Animal Research.
Treatment and experimental design
The rats were randomly divided into three groups consisting of six animals each. In group 1 (control group),
the rats received distilled drinking water. In group 2 (EG
group), they received hyperoxaluria-inducing 0.75%
ethylene glycol in distilled water. In group 3 (EG + PDTC
group), they were injected intraperitoneally (i.p.) with
PDTC (Sigma-Aldrich Chemical Corp, MO, USA) and
received 0.75% ethylene glycol in distilled water. PDTC
dissolved in distilled water and injected i.p. at the dose
of 100 mg/kg body weight. The doses of PDTC were
selected based on the results of recent studies where the
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Archivio Italiano di Urologia e Andrologia 2010; 82, 2
antioxidant and anti-inflammatory action of this agent
was apparent (26, 27).
Each of the major groups was then divided into three
groups according to the experimental sampling periods;
i.e., 7, 15, 45 days. After the last enjection, rats were
placed in metabolic cages to determine 24-hour urine
output, urinary pH and total urinary protein and oxalate
concentrations. At 24 hours after the last enjection, all
rats were killed with a high dose ketamine. The kidneys
were quickly removed and separated from surrounding
tissues and washed twice with cold saline solution, and
one of the kidneys were stored at -80 C° to determination the level of renal malondialdehyde (MDA), glutathione (GSH) and nitric oxide (NO). The other kidney
was stored in formaldehide solution for histopathological
and immunohistochemical examination.
Histopathological examination
Paraffin embedded specimens were cut into 6 (μm)
thickness and stained hematoxylin and eosin for light
microscopic examination (Olympus, BH-2, Tokyo,
Japan). The kidney sections were analysed semi-quantitatively using the technique of Houghton et al. (28).
Immunohistochemical studies
For imminohistochemical avaluation, specimens were
processed for light microscopy and sections incubated at
60 ºC overnight and then de-waxed in xylene for 30
minutes. After rehydrating in a decreasing series of
ethanol, sections were washed with distilled water and
PBS for 10 minutes. Sections were then treated with 2%
trypsin in 50 mM Tris buffer (pH 7.5) at 37 ºC for 15
minutes and washed with PBS.
Sections were delineated with a Dako pen (Dako,
Glostrup, Denmark) and incubated in a solution of 3%
H2O2 for 15 min to inhibit endogenous peroxidase activity. Then, sections were incubated with NF-kB/p65 (Rel
A) Ab-1 (R-B-1638-R7, Neomarkers, Labvision,
Fremont, CA, USA), MAPK/p38 (Vector Laboratories,
Burlingame, CA, USA), and iNOS Ab-1 (R-B-1605-R7,
Neomarkers) antibodies. The Ultra-vision (Labvision)
horseradish peroxidase /3-amino-9-ethylcarbazole staining protocol were used at this stage.
Sections prepared for each case were examined by light
microscopy. Sections of rat lung were used as the control
for immunohistochemical staining specifitiy, according
to data provided by the antibody manufacturer.
According to the diffuseness of the staining, sections
were graded as 0= no staining, 1= staining < 25%; 2=
staining between 25% and 50%; 3= staining between
50% and 75%; or 4= staining > 75%. According to staining intensity, sections were graded as 0= no staining; 1=
weak but detectable staining; 2, distinct; 3= intense
staining. Immunohistochemical values were obtained by
adding the diffuseness and intensity scores.
Transmission electron microscopy
Tissues were prefixed in 1% glutaraldehide and 4%
formaldehide in PBS for 2 hours. Then, the tissues were
postfixed in phosphate-buffered osmium tetraoxide for 1
hour (pH 7.2), dehydrated in a graded series of ethanol,
and embedded in Epon. Ultrathin sections were cut
NK-kB and p38-MAPK signaling in ethylene glycol induced urolithiasis
using a Reinheirt Om U3 ultramicrotome with glass
knives, stained with acetate and lead citrate, and examined using a carl Zeiss EM 9 S-2. Tissue sections were
scored on a four-point scale by two histologist unaware
of the treatment given and applying the scale to both the
medulla and the cortex. The scoring was as follows: 0=
no oxalate crystals in any field; 1= no more than two
crystals in any field; 2= more than two crystals in any
field; and 3= multiple collections of crystals in all fields.
nm in a spectrofluorometer, as described previously (30).
GSH level determination
GSH was determined by the spectrophotometric method,
which was based on the use of Ellman’s reagent (31).
Blood samples were also taken to asses the serum concentrations of urea, creatinine blood urea nitrogen
(BUN), Na+and K.+ All biochemical variables were
determined using an Olympus Autoanalyser (Olympus
Instruments, Tokyo, Japan).
Biochemical assesments
Nitric Oxide (NO) level
Total nitrite (NOx) was quantified by the Griess reaction
(29) after incubating the supernatant with Escherichia
coli nitrate reductase to convert NO3 to NO2. Griess
reagent (1 mL 1 % sulfanilamide, 0.1% naphtyl-ethylenediamine hydrochloride, and 2.5 % phosphoric acid;
Sigma Chemical Co., St. Louis, MO, USA) was then
added to 1 mL of supernatant. The absorbance was read
at 545 nm after a 30-min incubation. The absorbance
was compared with the standard graph of NaNO2,
obtained from the reduction of NaNO3 (1-100 µmol/L).
The accuracy of the assay was checked in two ways; the
inter-and intra- assay coefficients of variation were
7.52% and 4.61%, respectively. To check conversion of
nitrate to nitrite (recovery rate), known amounts of
nitrate were added to control plasma samples; these samples were deproteinised and reduced as above.
MDA level determination
Kidney tissue (300 mg) was homojenized in ice-cold tamponade containing 150 mM KCL for determination of
MDA. MDA levels were assayed for products of lipid peroxidation. MDA referred to as thiobarbituric acid reactive
substance, was measured with thiobarbituric acid at 532
Statistical analysis
Statistical analyses of the histopathologic and immunohistochemical evaluation of the groups were carried out
by the chi-square test and analyses of the biochemical
data by the Mann Whitney U- test. Results of all groups
were shown as mean values ± standard deviation (SD). P
< 0.05 was accepted as statistically significant value.
RESULTS
Biochemical variables in urine, serum and tissue
There was no significant differences in BUN, serum urea
and creatinine, Na+ and K+ concentrations 7, 15 or 45
days after administration in any of the groups (Table 1).
There were no marked changes between the control and
experimental groups in terms of daily urine output or
total urinary protein. The urinary pH was significantly
higher in the EG groups compared with the control and
EG + PDTC groups at all time points (p < 0.05, Table 1).
The 24-hour urinary oxalate excretion was significantly
higher in EG group than in the control and EG + PDTC
groups 7, 15 and 45 days after administration (p < 0.01).
In the EG + PDTC groups, 24-hour urinary oxalate
Table 1.
Serum and Urine variables in control, EG, and EG + PDTC rats.
Values are expressed as mean ± S.D. for six rats in each group.
Groups: Control, EG (Ethylene Glycol), and EG + PDTC ( Pyrrolidine Dithiocarbamate)
“a” compared with control group and “b” compared with EG group.
#P > 0,05
*P < 0,05
**P < 0,01
Archivio Italiano di Urologia e Andrologia 2010; 82, 2
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Özlem İlbey, E. Özbek, A. Şimşek, M. Cekmen, A. Somay, A.I. Tasci
Table 2.
The GSH, MDA and NO level in control, EG, and EG + PDTC groups.
Values are expressed as mean ± S.D. for six rats in each group.
Groups: Control, EG (Ethylene Glycol), PDTC (Pyrrolidine Dithiocarbamate)
“a” compared with control group and “b” compared with EG group.
*P < 0,05
**P < 0,01
excretion increased gradually after administration of the
substance began. The excretion in this group was higher
than in the controls, but the differences were not significant (p > 0.05, Table 1).
The MDA and NO levels were found to be significantly
lower (p < 0.01) and the GSH level was higher (p < 0.05)
in the renal tissues of the EG + PDTC groups compared
with the EG groups at all time points (Table 2).
Transmission electron microscopy
Transmission electron microscopy clearly showed calcium oxalate deposits in the kidneys of the EG groups 7,
15 and 45 days after administration Crystals deposits
were found in proximal tubules of the cortex. In the kidney sections of the rats treated with EG only on day 7,
oxalate particles were found in the renal cortex. Only rats
in EG groups calcium crystals in the renal sections, with
diffirent cyrstal amounts being found on day 15.
Cyrstals were found in all the renal cortex tips in all the
rats in the EG group on day 45. No crystal deposits were
detected in control groups at any time. There was limited or no crystal deposition in the rats treated with PDTC
on day 7, 15 and 45 (Table 3).
Histological examination
Light microscopy of renal cortex and medulla showed
Table 3.
Crystallization rates of groups.
Transmission electron microscopy clearly showed calcium oxalate deposits in the kidneys of the EG, EG+PDTC groups 7, 15 and 45 days after administration Crystals
deposits were found in proximal tubules of the cortex
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NK-kB and p38-MAPK signaling in ethylene glycol induced urolithiasis
Table 4.
The immunohistochemical staining score in control, EG, and EG+PDTC groups.
According to the diffuseness of the staining, sections were graded as 0= no staining, 1= staining < 25%; 2= staining between 25% and 50%; 3= staining between
50% and 75%; or 4= staining > 75%. According to staining intensity, sections were graded as 0= no staining; 1= weak but detectable staining; 2, distinct; 3= intense
staining. Immunohistochemical values were obtained by adding the diffuseness and intensity scores.
tubular epithelial cell degenaration, granular material in
the lumens of some tubules and mononuclear inflammatory cells infiltrating the interstitium.
These changes were more apparent in rats treated with
EG only than the others and were especially more prominent in on day 45.
Imminohistochemical studies
On immunohistochemical avaluation, there were more
intense expressions of iNOS, p38 MAPK and p65 NF-kB
in rats treated with EG alone compared with control at all
three times (Figure 1, Table 4). There were poor or slight
expressions of iNOS, p38 and p65 in the control and the
EG plus PDTC groups at all three times compared with the
EG groups Immunohistochemical scores of the rats treated
with EG alone on day 45 were the highest, and on day 15
were hihger than those on day 7, but there was no significant difference between the last two groups.
DISCUSSION
Urolithiasis is a complex process that is a consequence of
an imbalance between promoters and inhibitors in the kidneys (32). Considerable evidence has implicated ROS in
the pathophysiology of a wide spectrum of disorders,
including atherosclerosis, ischemia-reperfusion injury,
inflammatory disorders, cancer and aging (33). Similarly
association of urolithiasis and free radicals has been reported (4).
Many experimental models have been developed to
investigate the mechanisms involved in the formation of
urinary stones, and to ascertain the effect of various therapeutic agents on the development and progression of
the disease (34-36). Rats are the most frequently used
animals in models of CaOx deposition in the kidneys, a
process that mimics the etiology of kidney stone formation in humans (37). Rats models of CaOx urolithiasis
induced by EG alone or in combination with other
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Özlem İlbey, E. Özbek, A. Şimşek, M. Cekmen, A. Somay, A.I. Tasci
Figure 1.
Immunohistochemical staining showing iNOS, p65/NF-kB and p38/MAPK expression.
A) Focal mild staining (score 1) with iNOS in control (x 100);
B) Low NFkB/p65 positivity (score 2) in control (x 400);
C) Low MAPK/p38 positivity (score 2) in control (x 100);
D) Mild iNOS staining (score 3) in 7. Days EG (x 100);
E) Diffuse, intensive NFkB/p65 positivity (score 7) in 45. Days EG group (x 100);
F) Diffuse, intensive MAPK/p38 positivity (score 7) in 45. Days EG group (x 200);
G) Mild iNOS staining (score 3) in 15.Days EG+PDTC Group (x 100);
H) Low NFkB/p65 positivity (score 3) in 45.Days EG+PDTC Group (x 100);
I) Low MAPK/p38 positivity (score 3) in 15 Days EG+PDTC Group (x 100).
drugs, are often used to study the pathogenesis of kidney
crystal deposition (2, 35).
A lots of experimental evidence has suggested the role of
ROS in the pathophysiology of EG- induced urolithiasis in
rats, and several antioxidant agents have been used to prevent CaOx crystal deposition in the kidney (38, 39). Here
we measured the MDA, GSH, and total nitrite, a stable
product of nitric oxide (NO), as a means of oxidative
stress. The MDA and NO levels were found to be significantly lower and the GSH level was higher in the renal tissues of the EG + PDTC groups compared with the EG
groups at all time points. PDTC may prevent CaOx crystal
deposition in the kidney by preventing hyperoxaluriainduced peroxidative damage to renal tubular membrane
surface, which in turn can prevent CaOx crystal attachment and subsequent development of kidney stones. In
92
Archivio Italiano di Urologia e Andrologia 2010; 82, 2
adition of these oxidative stress parameters we also evaluated the expression of redox sensitive transcription factors,
NF-kB and MAPK, by immunohistochemistry.
Reverse transcriptase-polymerase chain reaction or
Western blotting analyses are functional assays by which
to measure the actual activity of iNOS. Western blotting
provides a more quantitative way of measuring iNOS and
p65 subunit activity. Therefore, it may be a limitation of
this study that Western blotting analyses were not performed. However, there are a number of studies in the
literature that have made use of immunohistochemical
grading of iNOS to evaluate NO activity (40).
Increasing evidence suggests that PDTC have not only
metal-chelating effect but also have thiol-modifying and
oxygen radical-scavenging antioxidative properties
mediate the inhibition of NF-kB (23). Since there is evi-
NK-kB and p38-MAPK signaling in ethylene glycol induced urolithiasis
dence that both the MAPK and NF-kB systems can be
activated by oxidative stress, we investigated the expression of p38-MAPK and NF-kB in the kidney in rats treated with EG alone or EG + PDTC. In present study, there
were more intense expressions of p38-MAPK and p65NF-kB in rats treated with EG alone compared with control, and there were poor or slight expressions of p38 and
p65 in the control and the EG + PDTC groups at all three
times compared with the EG groups.
It has been reported that p38-MAPK and NFκB pathways
are activated in a variety of experimental models of renal
inflammatory disease, including antiglomerular basement
membrane nephritis (42), ureteric obstruction (43), endotoxemia (44), and immun complex nephritis (45). Our
study shows that this also occurs in the kidney of rats with
nephrolithiasis induced by EG. We think that increased
ROS secondary to EG therapy in rat kidney causes the
degradation of its inhibitor Ik-B-alpha or proteolyticcleavage of p105 and free NF-kB dimers translocates to nucleus
and activates the target genes, such as iNOS. The iNOS is
one of the three NOS isoforms that is affected by NF-kB as
a result of tissue damage. The iNOS-mediated NO production is significantly elavated when there is increased oxidative stress (19, 47), and excessive NO production secondary to elevated expression of iNOS may impose cytotoxic
effects on various organs, including the kidney (48).
It has been reported that selective p38-MAPK inhibitors
can block the production of inflammatory molecules,
reducing the apoptotic cell death and ameliorating the
acute renal injury observed in some animal models of
renal disease such as anti-GBM glomerulonephritis and
ischemia/reperfusion (13,14). Furthermore, there is evidence that the production of TNF post-renal injury is
triggered by the locally produced ROS, which activate
NF-kB through p38 MAPK (51). Activation of p38MAPK can also induce NF-kB activation and subsequent
transcription of inflammatory cytokines (52). TNF-α
and ROS also activates NF-kB (53). In this study we can
suggest that calcium crystals activate p38-MAPK signal
transduction pathway in renal epithelial cells, and the
increased p38-MAPK activity further activates NF-kB
and plays essential role in innate inflammation.
Our data suggest that NF-kB and p38-MAPK signal
transduction pathway might serve as novel target in the
treatment of the inflammatory conditions involving calcium deposits. The blockade of NF-kB and MAPK activation by antioxidant could be an effective strategy for
the treatment and prophylaxis of urolithiasis in conditions such as hyperoxaluric states including primary
oxalosis or secondary hyperoxaluria can lead to renal
tubulointerstitial damage. PDTC attenuates EG-induced
nephrolithiais presumeably antioxydant as well as NF-kB
inhibitor properties. PDTC also can be used in clical
practice in hyperoxaluric patients who are in high risc
group for nephrolithiasis, but further animal and clinical
studies are needed to confirm our suggestion.
2. Khan SR. Animal models of kidney stone formation: an analysis.
World J Urol 1997; 154:236-243.
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Correspondence
Yusuf Özlem İlbey, MD
Department of Urology
Istanbul-Vakif Gureba Research & Education Hospital
Vatan Caddesi, 34095 - Aksaray, Istanbul, Turkey
[email protected]
Emin Özbek, MD
Department of Urology
Istanbul-Vakif Gureba Research & Education Hospital
Vatan Caddesi, 34095 - Aksaray, Istanbul, Turkey
[email protected]
Abdulmuttalip Şimşek, MD
Department of Urology
Istanbul-Vakif Gureba Research & Education Hospital
Vatan Caddesi, 34095 - Aksaray, Istanbul, Turkey
[email protected]
Mustafa Cekmen, MD
Department of Biochemistry
Kocaeli University
Istanbul, Turkey
Adnan Somay, MD
Department of Pathology
Istanbul-Vakif Gureba Research & Education Hospital
Vatan Caddesi, 34095 - Aksaray, Istanbul, Turkey
[email protected]
Ali Ihsan Tasci, MD
Bakırköy Research and Education Hospital
Istanbul, Turkey
ORIGINAL PAPER
Prostate cancer detection after one or more
negative extended needle biopsy:
Results of a multicenter case-findings protocol.
Pietro Pepe 1, Giuseppe Dibenedetto 2, Massimo Gulletta 3, Francesco
Pietropaolo 4, Giancarlo Minaldi 5, Venerando Gulino 6, Michele Barbera 7,
Salvatore Rotondo 8, Guido Azzarello 9, Franco Amico 10, Francesco Aragona 1
1 Urology
Unit, Cannizzaro Hospital Catania, Italy;
Unit, San Cataldo, Italy;
3 Urology Unit, Barcellona PG, Italy;
4 Urology Unit, Cefalù, Italy;
5 Urology Unit, Acireale, Italy;
6 Urology Unit, Comiso, Italy;
7 Urology Unit, Sciacca, Italy;
8 Urology Unit, Messina, Italy;
9 Ultrasound Unit, Policlinico Universitario, Catania, Italy;
10 Urology Unit, Ragusa, Italy
2 Urology
Summary
Objectives: To evaluate PCa incidence in patients with one or more negative extended
prostate biopsy who underwent repeat biopsy or TURP.
Material and methods: From June 2003 to February 2008, 308 patients were submitted to repeat prostate biopsy (median 20.5 cores) and 120 patients underwent TURP
after one or more 12 cores prostate biopsy. Indications for biopsy were: abnormal
DRE; PSA > 10 ng/mL; PSA included between 4.1-10 or 2.6-4 ng/mL with free/total PSA ≤ 25%
and ≤ 20%, respectively. 262 and 46 underwent a second and a third biopsy: 218 because for
high levels of PSA, 40 and 50 patients for a previous diagnosis of HGPIN and ASAP, 28 had an
abnormal DRE. PSA in patients who underwent TURP was 11.6 ng/mL (median); in all cases
DRE was negative and only 76 patients referred LUTS.
Results: PCa incidence at repeat biopsy was 16.9%; 96.2% of cancers were diagnosed at a second biopsy and 3.8% at a third one. PCa incidence was higher in patients with previous ASAP
(43.4% and 50%) vs patients with HGPIN (25% and 0%) or benign pathology (11.9% and 0%).
PCa was diagnosed in 11.1% and 19% of patients who underwent TURP previously submitted
to a first and a second biopsy, respectively.
Conclusions: In case of persistent suspicion of PCa after a repeated negative saturation biopsy, TURP should be proposed as part of the diagnostic procedure aside from LUTS, especially
in patients with a life expectancy greater than 10 years.
KEy wORDS: Prostate cancer, Extended prostate biopsy, TURP, Saturation biopsy, Repeat prostate biopsy..
Submitted 23 February 2009; Accepted 30 June 2009
INTRODUCTION
The widespread use of PSA in clinical practice has led to
an increased diagnosis of prostate cancer (PCa),
although the specificity of PSA levels less than 10 ng/mL
is rather poor (1). In order to improve the diagnostic
accuracy, some determinants of PSA kinetics (free to
total PSA ratio, PSA density and PSA velocity) along with
extended biopsy protocols have been introduced (2). In
spite of all, still some patients remain with a persistent
suspicion of harbouring a cancer despite multiple nega-
tive biopsies. In selected cases, some Authors proposed
a transurethral resection of prostate (TURP) as a part of
diagnostic procedure, lower urinary tract symptoms
(LUTS) aside (3).
In this prospective study we report the incidence of PCa in
428 patients, enrolled in a multicenter case-findings protocol, who, after one or more negative extended prostate
biopsy, underwent repeat biopsy or TURP because of a
persistent clinical suspicion of cancer.
Archivio Italiano di Urologia e Andrologia 2010; 82, 2
95
P. Pepe, G. Dibenedetto, M. Gulletta, F. Pietropaolo, G. Minaldi, V. Gulino, M. Barbera, S. Rotondo, G. Azzarello, F. Amico, F. Aragona
MATERIAL
AND METHODS
From June 2003 to February 2008, among 428
Caucasians patients, who previously underwent one or
more 12 cores prostate biopsy according to Ravery’s
scheme (2), an extended US-guided prostate biopsy was
performed in 308 of them (age range: 45-76 years; median 62.4) and a TURP in the remaining 120 patients (age
range: 53-78 years; median 68.4). Patients accepted to
be enrolled in a multicenter case-finding protocol for
PCa detection, signing an informed consensus form
which, in addition to the biopsy-related complications,
explicitely reported the risk of diagnosing a clinically
non significant PCa for low PSA levels and/or when a
greater number of cores are taken.
Indications for biopsy were: abnormal digital rectal
examination (DRE); total PSA (tPSA) greater than 10
ng/mL; tPSA between 4.1 and 10 ng/mL with percent
free PSA (%-fPSA) 25% or less; tPSA between 2.6 and 4
ng/mL with %fPSA 20% or less (4).
Among the 308 patients who were considered eligible
for an extended biopsy protocol, 262 (85%) and 46
(15%) underwent a second and a third procedure: in
218 (70.8%) because of persistent high levels of tPSA
and/or an abnormal %-fPSA; while 40 (13%) and 50
(16.2%) patients had a previous diagnosis of HGPIN and
ASAP, respectively. Overall, in these patients the median
tPSA was 9 ng/mL (range 2.9-36): 7.3 ng/mL in those
with a negative primary biopsy, 6.2 ng/mL in subjects
with previous HGPIN and 13.5 ng/mL in patients with
previous ASAP. Twenty-eight out of 308 (9.1%) had an
abnormal DRE (Table 1). Prostate biopsy was accomplished in a transperineal way supplied with a biplanar
transrectal probe with a tru-cut 18 G needle (Bard;
Covington, GA) under local anesthesia and antibiotic
prophylaxis; a median of 18 cores (range 12-23) were
taken from the peripheral region of the gland (apex, med
and base) and 2-4 cores (median 2.5) in the transition
zone.
Repeat biopsy was performed after an interval of 15.2
(second biopsy) and 16.5 (third biopsy) months in
patients with previous benign findings (chronic prostatitis or normal parenchyma) and approximately after 7
months in those who had a diagnosis of ASAP or HGPIN.
Three pathologists reviewed all cases.
To evaluate the role of TURP in diagnosing PCa after a
negative biopsy, a TURP was performed in 120 patients
with persistent elevated or rising PSA values: 36 (30%)
and 84 (70%) of them previously had one or two negative extended prostate biopsy, respectively. The median
tPSA was 11.6 ng/mL (range 2.7-36 ng/mL) and in all
cases DRE was negative; only 76 of these 120 men
(63.4%) complained LUTS (Table 1).
For statistical analysis the t Student’s-test was used; a p
value < 0.05 was considered statistically significant.
RESULTS
The median number of cores (peripheral + transition
zone) at repeat biopsy was 20.5 (range 14-26), whereas 35
grams (range 20-73) of tissue were removed by TURP.
Biopsy-related complications were: hematuria in
32 cases (10.4%), acute urinary retention in 26
Table 1.
cases (8.5%), hemospermia in 42 cases (13.6%),
Clinical parameters in patients who underwent repeat biopsy or TURP.
UTI in 19 cases (6.28%), orchiepididymitis in 2
cases (0.6%). No patients who underwent repeat
biopsy required hospitalization; in all patients
2nd biopsy
3rd biopsy
TURP
submitted to TURP the postoperative course was
Race
Caucasians
Caucasians
Caucasians
uneventful.
262 (85%) pts
46 (15%) pts
120 pts
Fifty-two cancers (16.9%) were found among 308
Age
45-76 years
49-73 years
53-78 years
men after repeat biopsy, most of them (50 PCa)
(median)
(63.2)
(60.2)
(68.4)
detected at a second biopsy and only 2 (3.8%) at
PSA 2.6-4.0 ng/mL
4
4
a
third one. Normal histology and chronic prosta(1.5%)
(3.3%)
titis was found in 189 (61.4%) and 67 (21.7%)
PSA 4.1-10 ng/mL
228
20
56
patients, respectively. The median Gleason score
(87%)
(43.4%)
(46.7%)
(GS)
was 6.4 (range 6-8) in men at a second biopPSA > 10 ng/mL
30
26
60
sy
(more
precisely, 30 patients had a GS equal to
(11.5%)
(46.6%)
(50.0%)
6, in 20 the GS was 7 and in 2 patients the GS was
Abnormal DRE
24
4
0
8); in both cancers detected at the third biopsy the
(9.2%)
(8.5%)
GS
was 6. After the second and the third biopsy,
Estimated median
52
58
46
the
incidence
of PCa was higher in patients with a
prostate weight
(31-100)
(42-86)
(30-90)
previous ASAP (43.4% and 50%, respectively)
(grams)
than in those with previous HGPIN (25% and 0%;
HGPIN
31
9
0
p = 0.005) and benign pathology (11.9% and 0%;
(11.8%)
(19.5%)
p = 0.0001) (Table 2). The median number of posASAP
44
6
0
itive cores was 2.8 (range 1-5) and 2 cores at sec(16.8%)
(13%)
ond and third biopsy, respectively. In two patients
LUTS
190
18
76
the cancer was localized only in the transition
(72.5%)
(39.2%)
(63.4%)
zone (third biopsy).
Qmax < 10 ml/sec
51
PCa was diagnosed in 20 out of 120 men (16.7%)
(42.5%)
who underwent TURP: 4 cases (11.1%) among
Post-void urinary
59
36 men who had a negative primary biopsy and
residual > 100 ml
(49.2%)
16 (19%) among the 84 patients who previously
96
Prostate cancer detection after one or more negative extended needle biopsy: Results of a multicenter case-findings protocol
comparison with 12 or 18 cores biopsy as an initial prostate biopsy strategy (9,10). Some parameters (time passed from the previous biopsy; previous HGPIN or ASAP) have been proposed to
PCa incidence
predict positive repeat biopsy for cancer (11),
Indications to biopsy
pts
PSA
at repeat biopsy
although a previous diagnosis of ASAP seems to
ng/mL
second
third
be the single risk factor that better relates with
(median)
(262 pts) (46 pts)
PCa. Scattoni et al. (12) showed a cancer in 39%
of 105 patients with a diagnosis of ASAP who
tPSA or %-fPSA
208
7.2
8.7%
0%
underwent a repeat biopsy reporting an even
(16)
higher risk in men with concomitant HGPIN
(50% of cases).
Abnormal DRE + PSA
10
9.2
3.2%
0%
How many biopsy sets and/or others procedures
(6)
such as TURP should be performed to rule out a
cancer, especially in younger patients we suspect
HGPIN
34
6.1
18.8%
0%
to harbour a PCa (persistently elevated or
(6)
increasing PSA values, previous HGPIN or
ASAP) is still under debate.
Abnormal DRE + HGPIN
6
6.8
6.2%
0%
Djavan et al. (13) reported a PCa incidence of
(2)
10%, 5% and 4% in patients with negative DRE
and PSA level of 4-10 ng/mL after a second, a
ASAP
38
13.0
28.2%
25%
third and a fourth sextant biopsy, respectively;
(13)
(1)
Philip et al. (14) and Singh et al. (15) showed an
incidence of PCa equal to 31.9% and 14% in
Abnormal DRE + ASAP
12
15.0
15.2%
25%
241 and 99 patients after a second 12 cores
(7)
(1)
biopsy; Satoh et al. (16) found a PCa in 25.7%
and 46.4% of 100 patients after a second and a
third biopsy. Kawakami et al. (17) showed a PCa
incidence of 37% in 235 patients using a 26
underwent two negative biopsy sets. The median Gleason
cores scheme with a three-dimensional TRUS guide and
score was 6 (range 4-7) in both groups.
this result was achieved after 16 cores. Eskicorapci et al.
In the remaining 100 patients, 85 (70.8%) and 15 (12.5%)
(18) reported an incidence of cancer higher in patients
had a diagnosis of BPH and prostatitis together with BPH,
previously submitted to a sextant biopsy (36.1%) than in
respectively. The clinical stage of cancers found by TURP
men who underwent primary 10 cores biopsy and they
was T1a in 18 cases (90%) and T1b in 2 cases (10%).
found a PCa in the transition zone only in 3.7% of cases.
Thirty months (range 6-48) after TURP, in the patients
SPBx increases the diagnosis of PCa during a repeated
with clinical stage T1a PCa, enrolled in an watchful waitbiopsy, but a greater number of cores increases the inciing programme, median tPSA was 0.9 ng/mL (range 0.4dence of low volume PCa (a single positive core or a neo1.3 ng/ml) whereas median tPSA in the patients with
plastic microfocus) with the consequent risk of overdiagbenign findings was 1.5 (0.8-3.4 ng/mL). The two patient
nosis/ overtreatment of clinically insignificant PCa, i.e.,
with clinical stage T1b PCa underwent radical prostatecless than 0.5 cc in volume without Gleason grade 4 or 5
tomy and surgical specimens showed a pT3aNo stage, a
disease (19). Fleshner and Klotz (20) reported a PCa
GS of 6 and 7 (3 + 4) and negative surgical margins.
incidence of 13% in 37 selected patients submitted to
Among the 20 patients with PCa found by TURP, only 11
SPBx after a negative second biopsy; Walz et al. (21)
(55%) complained preoperatively of LUTS.
showed a high incidence of cancer (41%) detected by
SPBx in 161 patients after previous negative biopsy sets;
Rabets et al. (22) reported 41% and 24% of PCa in 116
DISCUSSION
men previously submitted to 6 and 10 cores biopsy
The transrectal US-guided sextant prostate biopsy, proschemes; Rodriguez Alonso et al. (23) and Jones et al. (24),
posed by Hodge (5) in 1989, was considered the gold
using 24 cores extended biopsy, reported 40.8% and
standard in the diagnosis of PCa until it was demonstrat33% of cancer, respectively. In our experience (10) a PCa
ed that about 15-20 % of clinical significant cancers were
detection rate of 22.6% and 10.9% in 75 and 73 patients
missed (6), leading to the necessity of practicing several
submitted to SPBx and 18 core biopsy set after an initial
biopsy sets in a consistent number of patients. Today an
negative extended biopsy was found.
extended TRUS-guided biopsy scheme with an increased
A transition zone sampling is recommended at repeat
number of cores on the peripheral portion and on the
biopsy, though the PCa detection is low. Peizer et al. (25)
lateral margins of the gland is the only suitable method
and Miyake et al. (26) reported a detection rate equal to
to improve the detection rate of PCa (7). The incidence
1.8% and 5.3% in 1475 and 788 patients, respectively.
of cancer at repeat biopsy after an extended primary
On the contrary, a consistent number of PCa not found
prostate biopsy is lower than after a sextant biopsy (8);
by biopsy are subsequently diagnosed by TURP or open
however, the saturation prostate biopsy (SPBx) (i.e., 24
prostatectomy. Therefore many authors suggested to peror more cores), does not improve cancer detection rate in
form a TURP, after multiple negative biopsy series, even
Table 2.
Clinical parameters and PCa incidence at second and third biopsy.
Archivio Italiano di Urologia e Andrologia 2010; 82, 2
97
P. Pepe, G. Dibenedetto, M. Gulletta, F. Pietropaolo, G. Minaldi, V. Gulino, M. Barbera, S. Rotondo, G. Azzarello, F. Amico, F. Aragona
in men not complaining LUTS. Radhakrishnan et al. (27),
Zigeuner et al. (28) and Puppo et al. (3) after TURP reported a PCa detection of 21%, 7.9% and 42.8%, respectively. PCa diagnosed by TURP frequently originate in the
anterior prostate, are clinically confined with a GS < 6
suggesting that tumours located in the transition zone
have a less aggressive phenotype than those found in the
peripheral zone (29) and PSA measured before and after
TURP and GS are considered significant predictors of the
presence of residual cancer at radical prostatectomy (30).
In our experience, all PCa were diagnosed in the peripheral area of the gland during a second biopsy and only
two PCa (3.8%), located in the transition area, were
detected at a third biopsy set. In patients submitted to
repeat biopsy after a previous ASAP, the probability to
find a PCa was significantly higher than in patients
affected by HGPIN (p = 0.005) or with benign findings
(p = 0.001).
In patients submitted to TURP, PCa incidence was 11.1%
and 19% after one and two negative biopsies, respectively, showing an increasing risk of PCa detection in the
transition area even after multiple negative biopsies. The
extent of cancer in the tissue obtained by TURP allowed
to distinguish 18 patients with a T1a cancer, who were
enrolled in an watchful waiting programme, from 2
patients with a T1b cancer who underwent radical surgery. It is interesting that in all patients with clinical stage
T1a PCa PSA was stable (median 0.9 ng/mL) after a
median follow up of two years, suggesting that cancer
was localized exclusively in the transition zone. In the
majority of patients with benign findings after TURP, a
significant reduction of tPSA values (1.5 ng/ml; range:
0.8-3.4 ng/ml) was observed: this allowed to distinguish
patients with stable tPSA and normal DRE from those
with increasing tPSA who are still eligible for a repeat
biopsy. Specimen obtained by TURP allowed to stage
PCa suggesting radical surgery only in patients with clinical T1b PCa; on the contrary, it is a difficult task to
decide the best management, in presence of one or more
positive biopsy cores found only in the transition zone,
as prostatectomy could be an overtreatment.
In conclusion, in case of persistent suspicion of PCa after
a repeated negative saturation biopsy, TURP should be
proposed as part of the diagnostic procedure aside from
LUTS, especially in patients with a life expectancy greater
than 10 years.
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prostate cancer. J Urol 2000; 164:393.
3. Puppo P, Introini C, Calvi P, Naselli A. Role of transurethral resection of the prostate and biopsy of the peripheral zone in the same session after repeated negative biopsies in the diagnosis of prostate cancer. Eur Urol 2006; 49:873.
4. Aragona F, Pepe P, Motta M, Saita A, Raciti G, La Rosa P, et al.
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5. Hodge KK, McNeal JE, Terris MK, Stamey TA. Random systematic versus directed ultrasound guided transrectal core biopsies of the
prostate. J Urol 1989; 142:71.
6. Norberg M, Egevad L, Holberg L, Sparen P, Norlen BJ, Busch C.
The sextant protocol for ultrasound-guided core biopsies of prostate
underestimates the presence of cancer. Urology 1997; 50:562.
7. Pepe P, Aragona F. Prostate needle biopsy: 12 vs 18 cores. Is it necessary? Urol Intern 2005; 74:19.
8. Brossner C, Madersbacher S, de Mare P, Ponholzer A, Al-Ali B,
Rauchenwald M. Follow-up of men obtaining a six-core versus a
ten-core benign prostate biopsy 7 years previousely. World J Urol
2005; 23:419.
9. Jones JS, Patel A, Schoefield L, Rabets JC, Zippe CD, MagiGalluzzi C. Saturation technique does not improve cancer detection
as an initial prostate biopsy strategy. J Urol 2006; 175:485.
10. Pepe P, Aragona F. Saturation prostate needle biopsy and
prostate cancer detection at initial and repeat evaluation. Urology
2007; 70:1131-35.
11. Yanke BV, Gonen M, Scardino PT, Kattan MW. Validation of
nomogram for predicting positive repeat biopsy for prostate cancer. J
Urol 2005; 173:421.
12. Scattoni V, Roscigno M, Freschi M, Deho F, Raber M, Briganti A,
et al. Atypical small acinar proliferation (ASAP) on extended prostatic biopsies: predictive factors of cancer detection on repeat biopsies. Arch Ital Urol Androl 2005; 77:31.
13. Djavan B, Milani S, Remzi M. Prostate biopsy: who, how and
when. An update. Can J Urol 2005; 1:44.
14. Philip J, Hanchanale V, Foster CS, Javle P. Importance of peripheral biopsies in maximising the detection of early prostate cancer in
repeat 12-core biopsy protocol. BJU Int 2006; 98:559.
15. Singh H, Canto EI, Shariat SF, Kadmon D, Miles BJ, Wheeler
TM, Slawin KM. Predictors of prostate cancer after initial negative
systematic 12 core biopsy. J Urol 2004; 171:1850.
16. Satoh A, Matsumoto K, Nakamura S. Is interval from an initial
biopsy a significant predictor of prostate cancer at repeat biopsies?
Int J Urol 2006; 13:224.
17. Kawakami S, Okuno T, Yonese J, Igari T, Arai G, Fujii Y, et al.
Optimal sampling sites for repeat prostate biopsy: a recursive partitioning analisis of three-dimensional 26-core systematic biopsy. Eur
Urol 2007; 51:675.
18. Eskicorapci SY, Guliyey F, Islamoglu E, Ergen A, Ozen H. The
effect of prior biopsy scheme on prostate cancer detection for repeat
biopsy population: results of the 14-core prostate biopsy technique.
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19. Epstein J, Walsh P, Carmichael M, Brendler CB.Pathological and
clinical findings to predict tumor extent of non palpable (stage T1c)
prostate cancer. JAMA 1994; 271:368.
20. Fleshner N, Klotz L. Role of “saturation biopsy” in the detection of prostate cancer among difficult diagnostic cases. Urology
2002; 60:93.
21. Walz J, Graefen M, Chun FK, Erbersdobler A, Haese A, Steuber
T, et al. High incidence of prostate cancer detected by saturation
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22. Rabets JC, Jones JS, Patel A, Zippe CD. Prostate cancer detection with office based saturation biopsy in a repeat biopsy population. J Urol 2004; 172:94.
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Suarez Pascual G, Monelli Martin C, Lorenzo Franco J et al.
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Detection of prostate cancer by TURP or open surgery in patients with
previously negative transrectal prostate biopsies. Urology 2003; 62:883.
29. Sakai I, Harada K, Kurahashi T, Yamanaka K, Hara I, Miyake
H. Analysis of differences in clinocopathological features between
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Correspondence
Pietro Pepe, MD
U.O. di Urologia, Azienda Ospedaliera Cannizzaro
via Messina 829 - 95126 Catania, Italy
[email protected]
Dibenedetto Giuseppe, MD
Urology Unit, Ospedale Raimondi
via Forlanini - 93107 San Cataldo, Italy
Gulletta Massimo, MD
Urology Unit, Ospedale Cedroni Zodda
via Cattafi - 98051 Barcellona PG, Italy
Pietropaolo Francesco, MD
Urology Unit, Ospedale San Raffaele - G. Giglio,
Contrada Pietra Pollastra Pisciotta, Cefalù, Italy
Minaldi Giancarlo, MD
Urology Unit, Ospedale S. Marta e S. Vetera
via Baronia - 95014 Acireale, Italy
Gulino Venerando, MD
Urology Unit, Ospedale Regina Margherita
C. da Rastrella - 97013 Comiso, Italy
Barbera Michele, MD
Urology Unit, Azienda Osp. OCR
via Pompei - 92019 Sciacca, Italy
Rotondo Salvatore, MD
Urology Unit, Azienda Ospedaliera Papardo
Contrada Papardo - 98158 Messina, Italy
Azzarello Guido, MD
Ultrasound Unit, Policlinico Universitario
via Santa Sofia 6 - 95126 Catania, Italy
Amico Franco, MD
Urology Unit, Ospedale Civile M. Paternò Arezzo
p.zza Ospedale Civile 1 - 97100 Ragusa, Italy
Aragona Francesco, MD
Unità Operativa di Urologia, Azienda Ospedaliera Cannizzaro,
via Messina, 829 - 95126 Catania, Italy
Archivio Italiano di Urologia e Andrologia 2010; 82, 2
99
ORIGINAL PAPER
Is it possible to predict post-residual voided urine
by bladder scan before uroflowmetry – a useful
and timesaving test to reduce the number of non –
evaluable uroflow measurements?
Mauro Dicuio 1, Stepan Vesely 2, Tomas Knutson 2, Jan-Erik Damber 2,
Diego Ettore Cuzzocrea 3, Christer Dahlstrand 2
1 Department
of Urology, Sahlgrenska University Hospital, Göteborg, Sweden and Department of Urology,
Ospedale Maggiore CA Pizzardi, Bologna, Italy;
2 Department of Urology, Sahlgrenska University Hospital, Göteborg, Sweden;
3 Department of Urology, Ospedale Maggiore CA Pizzardi, Bologna, Italy
Summary
Objectives: Bladder-scan before uroflowmetry is useful to reduce non-evaluable Qmaxdata. A significant problem is to receive an adequate voided volume in uroflow-measurements. Aims of this study were 1- to confirm if pre-voiding bladder scan can reduce
the number of inadequate flow measurements, 2- to establish threshold values for prevoiding bladderscan volumes before and after different treatments options 3- to study
if it is possible to predict the post-residual voided volume.
Material and methods: 121 patients performed 2 uroflowmetry before and after different treatments. Bladder volume was measured by transabdominal ultrasound when the patient had the
sensation to void and after uroflowmetry to calculate residual urine. Same investigations were
repeated after different treatments.
Results: 21% of the patients had insufficient voided volume < 125 ml in 1st recording and 22%
in 2nd ; while 28% of the patient had a volume voided < 150 ml in 1st recording and 33% in 2nd.
There was a strong correlation between the pre-voiding measured volume and the voided volume (r = 0.801, p < 0.0001), linear regression analysis yielded 1st flow rate recording is VoidVol = 32.703 + (0.637 * Pre-Vol) and 2nd flow rate recording is Void-Vol = 16.264 + (0.704 *
Pre-Vol) (r = 0.855; p < 0.0001).
Conclusions: Bladder scanning before uroflowmetry reduces the number of non-evaluable Qmax
data. If a voided volumes of > 125 ml (> 150 ml) is required a mandatory pre-voiding bladder
scan volume should be > 200 ml (> 250 ml), so non elegible Qmax recordings will decrease from
21% to 5.8% (28% to 4.1%) in BPH patients who will undergo treatment and from 22% to 7.4%
(33% to 5.8%) in BPH-treated patients. There is a difference between patients before and after
treatment. It is not possible to predict the post residual voided volume by the bladder scan using
the virtual calculation.
KEY WORDS: Bladder ultrasound scanning; Uroflowmetry; BPH studies; Minimum voided volume.
Submitted 23 February 2009; Accepted 30 June 2009
List of abbreviations:
LUTS: lower urinary tract symptoms.
BPH:
benign prostatic hyperplasia.
Qmax: maximum flow rate obtained during free-flow measurement.
PSA:
prostate specific antigen.
BPO:
benign prostatic obstruction.
IPSS:
international prostate symptoms score.
QoL:
quality of life.
TRUS: transurethral utrasound.
Pre-Vol: pre-voiding measured volume.
Void-Vol: voided volume.
100
Archivio Italiano di Urologia e Andrologia 2010; 82, 2
Bladder scan before uroflowmetry
INTRODUCTION
The use of bladder scanning before uroflowmetry recording seems to be a useful test to reduce the number of
non-evaluable Qmax data because of insufficient voided
volume (1, 2). A significant problem in clinical studies of
lower urinary tract symptoms (LUTS) due to bladder
outlet obstruction (BOO) is to receive an adequate voided volume in uroflow measurements. Ultrasound bladder scanning is not a test performed just by radiologist to
study the bladder; in fact it could be used in calculating
the post residual voided volume by measurement of urinary bladder volume (3) by an urologist or a nurse and
it could evaluate the prostatic intravesical protrusion correlated with uroflowmetry, this a new method to measure
obstruction in patients with LUTS due to BOO without
using Pressure/Flow studies (4). Benign prostatic hyperplasia and benign prostatic enlargement are one of the
most common diseases in aging men which can lead to
lower urinary tract symptoms (5). The clinical use of the
urine flowmeters, simple non-invasive investigation, has
become widespread to reveal abnormal voiding. Practice
Guideline shows that correct uroflowmetry needs a voided volume > 125-150 ml and Qmax is better than Qmean
and more specific to identify BPH patients (6).
Uroflowmetry is a recommended investigation as a diagnostic test in the initial assessment of men with LUTS
and should always be performed prior prostatic surgery.
Post-void residual volume urine measurement is also recommended, Post-void residual volumes > 200 ml may
indicate bladder dysfunction and predict a less
favourable response to treatment (5).
The aims of this study were 1- to confirm if pre-voiding
bladderscan can reduce the number of inadequate flow
measurements in patients with LUTS due to BOO, 2- to
establish threshold values for pre voiding bladder scan
volumes before and after different treatments options 3to study if it is possible to predict the post residual voided volume calculating the virtual post residual volume.
MATERIAL
AND METHODS
A total of 121 BPH patients with a mean age of 69.2 + 8.7
SD (range 46-88) years entered this study performing
two flow rates before and after different BPH treatments.
Initial patient evaluation consisted in medical history, urological visit including digital rectal examination and history of the patient taken from his clinical journal. Routine
blood chemistry included PSA, hemoglobin and creatinine.
Prostate size was assessed by transrectal ultrasonography
(probe of 7.5 MHz) and the prostatic volume calculated
using the formula considering length, width and height
and adjusting with π/6.
Bladder volume was measured by transabdominal ultrasound (3.5 MHz probe) when the patient had the sensation of need to void and after the uroflowmetry to calculate and measure residual urine. Bladder volume calculation was performed using the ellipsoid formula (A x B x
C x 0.52) as simple as possible just marking with the
cursor the peripheral area of the largest sagittal bladder
image and the maximal diameter. We have used this
method because the transverse diameter is the most difficult to measure and formulas that use transverse diameter show great inaccuracy in inexperienced hands
(1, 3). Thus after assessment the patients were treated
according to the severity of the disease: watchful waiting,
medical therapy, surgical management and minimally
invasive treatment.
Post residual voided volume was calculated by bladder
scan volume after uroflowmetry and also subtracting the
bladder scan before uroflowmetry to the voided volume
at uroflowmetry.
Conventional statistical methods were used to calculate
the mean and standard deviation using computer software and parameter analyses were calculated using simple linear regression test.
RESULTS
All the 121 patients concluded the study. A baseline
prior to treatment mean IPSS was of 17.0 + 9.2 (range 135) points, a mean QoL of 3.2 + 1.8 (range 0-5) points,
a serum PSA of 4.3 + 3.9 (range 0.4-20) ng/ml and a
serum creatinine of 112.8 + 19.0 (range 80-196), a TRUS
volume of 50.0 + 25.4 (18 to 166) cc After the different
Table 1.
121 patients were divided into 4 groups (> 125 ml, > 150 ml, > 200 ml, > 250 ml) according to pre-voiding measured volumes
(Pre-Vol). Voided volumes (Void-Vol) were then assessed in two different times (1st flow rate recording and 2nd flow rate recording).
Patients with insufficient voided volume (< 125 ml and < 150 ml) in each group was calculated.
1st flow rate recording
2nd flow rate recording
Pre-Vol
Void-Vol < 125
Void-Vol < 150
Void-Vol < 125
Void-Vol < 150
///
25/121 = 21%
34/121 = 28%
26/121 = 22%
40/121 = 33%
> 125 ml
15/121 = 12%
///
16/121 = 13%
///
> 150 ml
12/121 = 10%
20/121 = 17%
12/121 = 10%
24/121 = 20%
> 200 ml
7/121 = 5,8%
10/121 = 8.3%
9/121 = 7.4%
19/121 = 15.7%
> 250 ml
4/121 = 3,3%
5/121 = 4.1%
5/121 = 4.1%
7/121 = 5.8%
Archivio Italiano di Urologia e Andrologia 2010; 82, 2
101
M. Dicuio, S. Vesely, T. Knutson, J.-E. Damber, D.E. Cuzzocrea, C. Dahlstrand
ficient voided volume < 125 ml in
the first flow rate recording and
22% in the second; while 28% of
the patient had a volume voided
< 150 ml in the first flow rate
recording and 33% in the second
measurement.
We have divided the pre-voiding
measured volume (Pre-Vol) (see
Table 1) into 4 categories: > 125
ml, > 150 ml, > 200 ml, > 250 ml
and we have shown the relationship with the voided volume. Then
we have counted the number of
measurements with voided volume
< 125 ml and < 150 ml in the first
flow rate recording and in the second recording after the treatment.
There was a strong correlation
between the pre-voiding measured
volume (Pre-Vol) and the voided
volume (Void-Vol) at 1st uroflowmetry (r = 0.801, p < 0.0001),
Linear regression analysis yielded
1st flow rate recording is Void-Vol =
scann 1st
32.703 + (0.637 * Pre-Vol) (Figure
1). A good correlation (r = 0.855;
p < 0.0001) has been found also
between the pre-voiding measured
Figure 2.
Linear regression analysis yielded 2nd flow rate recording is
volume (Pre-Vol) and the voided
Void-Vol = 16.264 + (0.704 * Pre-Vol) (r = 0.855; p < 0.0001).
volume (Void-Vol) at 2nd uroflowmetry, Linear regression analysis yielded 2nd flow rate recording is
Void-Vol = 16.264 + (0.704 * PreVol) (Figure 2).
As we can see in the same table not
useful flow rate (voided volume <
125 ml) in the first flow rate
recording decreases from 21% to
12% and from 22% to 13% in the
2nd record if Pre-Vol was > 125 ml;
if Pre-Vol was > 150 not useful
Qmax decreased to 10% in both the
1st and 2nd records and decreased
to 5.8% and 7,4% in the 1st and 2nd
record respectively if Pre-Vol was >
200 ml.
Finally not useful flow rate decreased to 3,3% and to 4.1% in the
1st and 2nd record respectively if
Pre-Vol was > 250 ml. Important
percentage reduction has been
scann 2nd
obtained considering not useful
flow rate with voided volume < 150
ml from 28% to 17%, 8.3% 4.1%
in the 1st record and from 33% to
treatments mean IPSS was 10.8 + 7.5 (range 0-31)
20%, 15.7%, 5.8% in the 2nd flow rate recording if Prepoints, mean QoL was 1.8 + 1.6 (range 0-5) points,
Vol was > 125, 150, 200 and 250 ml respectively.
mean Qmax 12.3 + 5.7 (range 1-35) ml/s, mean PVR 74 +
Mean bladder scan volume in the first measurement was
75 (range 0-510) cc. We had responders and non
300 + 150 (range 50-800) ml, in the second measureresponders to the different treatments options.
ment was 282 + 143 (range 50-900) ml. Mean post voidIn our records, see table 1, 21% of the patients had insufed residual volume calculated by ultrasound was in the
volume 2nd
volume 1st
Figure 1.
Linear regression analysis yielded 1st flow rate recording is
Void-Vol = 32.703 + (0.637 * Pre-Vol) (r = 0.801; p < 0.0001).
102
Archivio Italiano di Urologia e Andrologia 2010; 82, 2
Bladder scan before uroflowmetry
first measurement 81 + 91 (range 0-600) ml and in the
second measurement was 74 + 75 (range 0-510) ml.
Mean voided urine volume calculated at uroflowmetry
was in the first measurement 224 + 119 (range 33-737)
ml and in the second measurement was 215 + 118 (range
33-698) ml. Mean virtual post voided residual volume
calculated by mathematical substraction between bladder scan prior to uroflowmetry and voided volume was
in the first measurement 76 + 89 (range -37-593) ml and
in the second measurement was 67 + 74 (range -45-506)
ml. There was statistical significant difference according
to the Paired t-test between Post residual voided volume
calculated by bladder scan after uroflowmetry and subtracting the bladder scan volume before uroflowmetry to
the voided volume at uroflowmetry, p < 0. 0046 in the
first measurement and p < 0.0002.
DISCUSSION
Benign Prostatic Hyperplasia, Benign Prostatic Enlargment
and Benign Prostatic Obstruction can be considered progressive disease based on published data on consequences
and complications of the disease. With a changing demographic profile and an increasingly aging population in
almost all societies it is estimated that one third of all men
will need a treatment for relief of LUTS due to benign prostatic obstruction (BPO). These man should be investigated to identify patients at risk of progression and to initiate
early preventive treatment (5).
Thus, research should be addressed also to improve
accuracy and to optimize the recommended diagnostic
test as uroflowmetry. To our knowledge few studies are
available to provide evidence that pre-voiding transabdominal ultrasound bladder scanning is useful before the
BPH patient undergoes free flow for BPH study before
and after treatment (1, 2). Even if there is a widespread
acceptance that a single free uroflow measurement is
unsatisfactory, most clinicians and studies rely on this.
We know that in the daily practice uroflowmetry test is
time consuming both for the patient and for the
nurse/doctor who is responsible for the test. Free
uroflowmetry give evidence of urinary dysfunction
although it has poor diagnostic specificity for BPO.
Other methods are not reliable as home uroflowmetry in
studies including large number of patients both for economical and organisation problems (7).
If we would have conducted a clinical assessment using
our flow rate records we would have lost 21% of the
patients at baseline because of insufficient voided volume < 125 ml for the first flow rate recording and the
22% in the first screening after the treatment; while 28%
of the patients had a volume voided < 150 ml at baseline
flow rate recording and 33% in the second measurement
after the treatment to not lose so many patients we probably would have been asking to the patient to repeat the
measurement. The patient would have lost time in the
clinic and interest in the following visit of follow up with
risk of losing the patient.
In comparison of Roehrborn et al. study and as confirmed
in the previous study (1) we have achieved higher
threshold volumes. Our patients data are, in our opinion,
interesting because both at the first and at the second
visit they represent a variety of BPH patients from
obstructed to unobstructed ones and from responder to
non responders with four times more measurements
data. Using the threshold of Roehrborn et al. we would
have lost too many patients (2).
It is not possible to predict the post residual voided volume in the way of measuring the bladder volume before
uroflowmetry instead measuring the volume after the
examination, in fact using a simple mathematical subtraction it is possible to calculate the virtual post residual
voided volume but the result sometimes is negative with
no possibility to have a clinical significance or sometimes
the result has a significant difference between the reality
the virtual calculation.
An explanation is that the volume obtained in this way is
indirect and contains error of approximation. For this
reason even if the calculation of the post voided residual
urine by ultrasounds is a good method recommended by
EAU BPH Guideline (5) it is not very precise as demonstrated by Simforoosh N et al. (8) For this reason nowadays several modern and technological methods exists
and are proposed (9). It is not possible to avoid the
measurement of the post voided urine volume after
uroflowmetry. Determination of the residual urine volume could be done in different ways in the routine practice in urology. Calculation of the residual urine volume
by catheterization, either transurethrally or sovrapubic,
despite its accuracy, is an invasive procedure that it could
have side effects and risk of infection. Radiological and
isotopic methods for bladder volume calculation are
inaccurate, may have radiation hazards and expensive.
For these reason Ultrasound urinary bladder volume
measurement is an easy calculation of bladder volume
and it is relatively precise (3).
Time consuming is almost the same but with the opportunity to reduce significantly the number of nonevaluable Qmax we truly recommend bladder scan before
uroflowmetry.
Bladder scanning is cost-effective and is also easy to perform, a well-instructed nurse is able to do the measurement. Time can also be saved both for the patient and for
the clinical management.
CONCLUSION
The use of bladder scanning before uroflowmetry recording is a useful test to reduce the number of non-evaluable
Qmax data. If a voided volumes of > 125 ml (> 150 ml) is
required a mandatory pre-voiding bladder scan volume
should be > 200 ml (> 250 ml), so the number of non
eligible Qmax recordings will decrease from 21% to 5.8%
(28% to 4.1%) in BPH patients who will undergo treatment and from 22% to 7.4% (33% to 5.8%) in BPHtreated patients. There is a difference between patients
before and after treatment. Unfortunately it is not possible to predict the post residual voided volume by the
bladder scan using the virtual calculation.
REFERENCES
1. Dicuio M, Creti S, Di Campli A, et al. Usefulness of a prevoiding
transabdominal sonographic bladder scan for uroflowmetry in
Archivio Italiano di Urologia e Andrologia 2010; 82, 2
103
M. Dicuio, S. Vesely, T. Knutson, J.-E. Damber, D.E. Cuzzocrea, C. Dahlstrand
patients involved in clinical studies of benign prostatic hyperplasia.
J Ultrasound Med 2003; 22:773.
2. Roehrborn CG, Djavan B, Gapin T, et al. Pre-voiding bladder volume ultrasound scanning as an adjunct test in clinical BPH studies:
impact on likelihood of achieving threshold volumes. Eur Urol 1999;
35(suppl. 2):115.
3. Dicuio M, Pomara G, Fabris FM, et al. Measurements of urinary
bladder volume: comparison of five ultrasound calculation methods
in volunteers. Arch Ital Urol Androl 2005; 77:60.
4. Dicuio M, Pomara G, Vesely S, et al. The use of prostatic intravesical protrusion correlated with uroflowmetry: a new method to
measure obstruction in patients with LUTS due to BOO without
using P/F studies. Arch Ital Urol Androl 2005; 77:50.
5. Madersbacher S, Alivizatos G, Nordling J, et al. EAU Guidelines
Correspondence
Marco Dicuio, MD
Via Morandi 43
56124 Pisa, Italy
[email protected]
Stepan Vesely, MD
Department of Urology,
Sahlgrenska University Hospital,
Göteborg SE-413 45, Sweden
Tomas Knutson, MD
Department of Urology,
Sahlgrenska University Hospital,
Göteborg SE-413 45, Sweden
Jan-Erik Damber, MD
Department of Urology,
Sahlgrenska University Hospital,
Göteborg SE-413 45, Sweden
Diego Ettore Cuzzocrea, MD
Department of Urology, Ospedale Maggiore CA Pizzardi,
largo Bartolo Nigrisoli - 240133 Bologna, Italy
Christer Dahlstrand, MD
Department of Urology,
Sahlgrenska University Hospital,
Göteborg SE-413 45, Sweden
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Archivio Italiano di Urologia e Andrologia 2010; 82, 2
on assessment, therapy and follow up of men with lower urinary
tract symptoms suggestive of benign prostatic obstruction (BPH
guidelines). Eur Urol 2004; 46:547.
6. Abrams PH, Torrens M. Urine flow studies. Urol Clin North Am
1979; 6:71.
7. Boci R, Fall M, Walden M, et al. The home uroflowmetryImproved accurancy in outflow assessment. Neurourol Urodyn
1998; 18:25.
8. Simforoosh N, Dadkhah F, Hosseini SY, et al. Accuracy of residual
urine measurement in men: comparison between real-time ultrasonography and catheterisation. J Urol 1997; 158:59.
9. Riccabona M, Nelson TR, Pretorius DH, et al. In vivo three-dimensional sonographic measurement of the organ volume:
validation in the urinary bladder. J Ultrasound Med 1996; 15:627.
ORIGINAL PAPER
Sarcoma of prostate:
Case report and review of the literature.
Gianna Pace 1, Roberto Pomante 3, Carlo Vicentini 1, 2
1 Department
of Health Sciences, University of L’Aquila, L’Aquila;
of Urology, Mazzini Hospital, Teramo;
3 Department of Pathology, Mazzini Hospital, Teramo, Italy
2 Department
Summary
Objectives: Prostate sarcomas are rare entity, the most common is leiomyosarcoma
which account for 0.1% of all prostate malignancies. The presenting symptoms are
mainly obstructive urinary symptoms. Surgery with chemo- or radiotherapy are the
mainstay treatment options. The overall survival rate remains poor regardless of initial tumour size, grade or histological subtype. Immunohistochemistry reveals tumour
cells diffusely positive for vimentin, smooth muscle actin, focally positive for progesterone
receptor, whilst keratins are usually negative.
Materials and Methods: We describe a case of a patient affected by sarcoma of prostate.
Furthermore, we reviewed the cases of prostate sarcomas available in literature to clarify the
best therapeutic options to be applied.
Results: In the case described leiomyosarcoma diagnosed by an ultrasound guided biopsy was
characterized by fascicles of spindle-shaped cells with a variable degree of nuclear atypia. The
immunohistochemistry showed positive staining for smooth muscle actin, vimentin and focally
for the S-100 protein. The patient was treated with radical retropubic prostatectomy and radiotherapy of the local recurrence, and chemotherapy at metastases onset.
Conclusions: Prostate sarcomas are highly aggressive, with limited therapeutic options. An
early diagnosis and complete surgical excision with negative margins offer patients the longterm disease free survival.
KEY WORDS: Sarcoma; Prostate; Leiomyosarcoma.
Submitted 5 November 2009; Accepted 30 December 2009
INTRODUCTION
Sarcomas of soft tissues (STS) are a heterogeneous group
of tumours arising from mesoderm. STSs of genitourinary tract (GU) are uncommon, accounting for 2% of
STSs and representing just 1-2% of the urological malignant cancers (1). In the two largest series available,
leiomyosarcoma followed by liposarcoma and rhabdomyosarcoma are reported to be the most common histological types (1, 2). Focusing on prostate, leiomyosarcoma represents less than 0.1% of all prostate malignancies and 38-52% of primary prostatic sarcomas, with a
mean age at presentation of 61 years (range 41-78 years)
(3-6). 89.4% of prostate sarcomas showed obstructive
urinary symptoms as first manifestation followed by perineal or rectal pain in 25.6% of patients, burning on ejaculation and hematuria in 5.2% of cases (7, 8). In about
23.5% of patients the metastatic signs may be the pre-
senting manifestations mainly involving lungs (17.6%),
liver (11.7%), bone (5.8%) and brain (3.6%) (7).
Local recurrences (LR) of GU STS range from 21% to
32% (1, 9). The different LR rates may be accounted to
biology, tumour size, patients selection, anatomical location. The biological aspects (grade, size, histology) are
key factors for metastatic progression as well as age at
presentation and histology are determinant in the metastases onset (1). Tumour histological grade, a well recognized adverse prognostic factor, is classified as low or
high based on the number of mitoses, degree of cellularity, differentiation and nuclear pleomorphism (9-11).
Predictors of disease specific survival are clinical local
presentation, complete tumour resection, tumour grade,
size, location and histological subtype. Patients with visceral and retroperitoneal sarcomas show a decreased surArchivio Italiano di Urologia e Andrologia 2010; 82, 2
105
G. Pace, R. Pomante, C. Vicentini
vival in respect to the extremity sarcomas
(10, 12). In addition, negative surgical margins are associated to freedom from LR and
from metastases as well as to a prolonged
survival (13). The reported disease specific
survival at 5 years was variable in relation
to the anatomical site ranging from 69 to
76% (1, 9, 10). Prostate sarcoma shows a
worse disease free survival of 38% than the
other STSs (10). The mainstay of STS treatment is complete surgical excision combined with radio- and chemotherapy. We
describe the clinical characteristics of a
leiomyosarcoma of the prostate presenting
with unusual symptoms and normal serum
prostate specific antigen (PSA). Moreover,
we reviewed prostate sarcoma histological
features and therapeutic options available.
MATERIALS
AND
Figure 1.
Leiomyosarcoma (H&E). The tumour is composed of a dominant
component of interlacing fascicles of spindle-shaped cells, with elongated,
blunt ended and pleomorphic nuclei. Of note two benign entrapped
prostatic glands (showed by the tip of the arrow).
METHODS
A 62-years-old white man presented with
frequent micturation, dysuria, poor urinary
stream and nocturia of approximately ten
months duration. He did not refer a family
history of GU cancers. He was not a smoker or an abuser of alcohol. PSA was 1.60
ng/ml. Rectal examination (RE) revealed an
enlarged prostate gland with a nodular mass
extended to the right and left lobe which led
to an ultrasound guided transrectal needle
biopsy.
Figure 2.
Negative staining for keratins (AE1-AE3) which are expressed just
in 25% of prostate sarcomas. Note that the benign gland
on the upper right corner shows a positive staining.
RESULTS
The histological diagnosis was leiomyosarcoma. The tumour was characterized by
areas of haemorrhage and necrosis, with
focal bilateral extracapsular extension. At
immunohistochemistry with H&E an high
hypercellularity with interlacing fascicles of
eosinophilic spindle-shaped cells with
blunt-ended nuclei and a variable nuclear
atypia with several mitosis were showed
(Figure 1). Prostate cells expressed
vimentin, smooth muscle actin and desmin
as well as S-100 while immunostaining for
keratins AE1-AE3 was negative (Figure 2).
The bone scan, chest X-ray and total body
computerized tomography (CT) were unremarkable. He underwent to a radical
retropubic prostatectomy (RRP) with bilateral lymphadenectomy. The tumour was multifocal and
bilateral, involving 76% of the prostate with surgical
margins free from tumour and lymph nodes of the external, internal iliac and obturator area negative. 3 years
after, he presented with acute urinary retention and an
urethrocystoscopy visualized an irregular necrotic tissue
growth. A permanent urinary catheter was placed. A
magnetic resonance spectroscopy (MRS) showed a local
recurrence and an enlarged left iliac lymph node. A palliative external-beam radiotherapy was recommended.
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Archivio Italiano di Urologia e Andrologia 2010; 82, 2
The diagnosis of left lung metastasis led to a chemotherapy which was prematurely interrupted as his general
status declined. He died 3 months later.
DISCUSSION
Sarcoma of prostate arises from non-epithelial mesenchymal components with several theories concerning
its origin from an incidental simultaneous development
of both carcinoma and sarcoma from different areas of
Sarcoma of prostate an unusual finding
the gland, a dissimilar differentiation from the same
totipotent cell, a transformation of an adenocarcinoma in
sarcoma or otherwise of a sarcoma in adenocarcinoma
(14-19). Mostofi and Price defined carcinosarcoma as a
prostatic adenocarcinoma with evidences of metaplastic
cartilaginous or osseous sarcoma (20). More recently
Young et al. described carcinosarcoma as a mixture of
epithelial elements and spindle cells associated to heterogeneous tissues such as cartilage or skeletal muscle
(21). Cytogenetic analysis of primary leiomyosarcoma
revealed clonal chromosomal rearrangement involving
chromosomes 2, 3, 9, 11, 19 (19). Stromal sarcoma
expresses CD34, less frequently smooth muscle and keratin markers; sarcomatoid prostatic carcinoma is characterized by malignant epithelial cells with the appearance
of spindle cells, expresses keratins and vimentin but no
desmin and actin (20). Carcinosarcoma of prostate and
other mixed-patterns arise from uncommitted stem cells
which differentiate in mesenchymal or epithelial elements (21).
The most common presenting manifestations are the
obstructive urinary symptoms: urgency, nocturia, hematuria, frequency, perineal or rectal pain and constipation.
PSA is typically within normal limits and it is not surprising considering the non-epithelial origin of prostate
sarcoma. The most frequent sarcoma of prostate is
leiomyosarcoma in the adult whereas rhabdomyosarcoma is more common in children and adolescents (4, 6).
Histological characteristics are high cellularity, bundles
of eosinophilic spindle-shaped cells, increased mitotic
activity and nuclear atypia, necrosis and cystic degeneration (5). Neoplastic cells exhibit vimentin, smooth muscle actin, and desmin (60%) while keratins are observed
just in 25% of cases (3). Progesterone receptor should be
also found whereas CD117 is absent; S-100 protein
immunoreactivity can be seen focally (22).
In most patients diagnosis is made by transurethral
resection (TURP) performed for obstructive urinary
symptoms or acute urinary retention, however it may be
missed if the sarcoma is not resected. A third of them
show demonstrable metastases at presentation mainly
located at the lung and liver (4, 6). MRS is characterised
by a marked increase in the ratio of choline: citrate; this
should be helpful in the differentiation with benign prostatic hyperplasia but unsuitable to differentiate prostate
sarcoma from carcinoma as the MRI features are similar.
At MRS adult prostate sarcoma typically appears as a
large cystic and necrotic mass, with rapid growth, hypervascular, with a heterogeneous tissue enhancement (23).
Lack of awareness of this rare tumour may responsible of
a delayed diagnosis, mainly caused by the unrelated
symptoms and normal serological markers. In the case
reported, the symptoms suggestive of prostate benign
enlargement and PSA normal value should be misleading; unlikely these are the most frequent prostate sarcoma presenting manifestations. Results related to tumour
grade, size and stage as predictors of long-term survival
are not homogeneous. Those differences are to be
accounted to the period of enrolment with inadequate
clinical staging due to inferior imaging capacities in earlier decades respect to more contemporary series and to
the different selection criteria including all GU STS or
just prostate sarcomas. An uniform agreement is related
to the significantly improved disease-free survival of
patients with negative surgical margins (2-4). Our
patient showed at diagnosis a focal extracapsular extension and was free from metastases allowing to perform a
RRP. A LR three years after, led to a combined radiochemotherapy. An hypothesized survival advantage may
be offered by combining several treatments based on preoperative chemoradiation followed by surgical excision
(24). A preoperative chemotherapy may be offered to
patients at high risk of positive surgical margins (4, 25).
Of note, the only predictive factors of long-term survival
were absence of metastases and negative surgical margins
(2, 4, 26, 27).
CONCLUSIONS
Prostate sarcoma is a very rare but highly aggressive cancer with limited therapeutic options: an early diagnosis is
mandatory to offer patients the best chance for cure. A
multidisciplinary approach including urological, radiotherapist and oncological consultations should be
employed for an appropriate management. The awareness of its existence and of its clinical manifestations may
achieve a correct diagnosis.
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3. Cheville JC, Dundore PA, Nascimento AG, et al. Leiomyosarcoma
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11. Kattan MW, Leung DH, Brennan MF. Postoperative nomogram
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12. Clark MA, Fisher C, Judson I, et al. Soft-tissue sarcomas in
adults. N Engl J Med 2005; 353:701-11.
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13. Catton CN, O’Sullivan B, Kotwall C, et al. Outcome and prognosis in retroperitoneal soft tissue sarcoma. Int J Radiat Oncol Biol
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LH, eds. Atlas of tumour pathology. Washington DC, Armed Forces
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14. Sen SE, Malek RS, Farrow GM, et al. Sarcoma and carcinosarcoma of the bladder in adults. J Urol 1985; 133:29-30.
22. Limon J, Dal Cin P, Sandberg AA. Cytogenetic findings in a primary leiomyosarcoma of the prostate. Cancer Genet Cytogenet
1987; 22:159-67.
15. Coleman J, Brennan MF, Alektiar K, et al. Adult spermatic cord
sarcomas: management and results. Ann Surg Oncol 2003; 10:669-75.
16. Khoubehi B, Mishra V, Ali M, et al. Adult paratesticular
tumours. BJU Int 2002; 90:707-15.
17. Dundore PA, Cheville JC, Nascimento AG, et al. Carcinosarcoma
of the prostate. Report of 21 cases. Cancer 1995; 76:1035-42.
18. Ginesin Y, Bolkier M, Moskovitz B, et al. Carcinosarcoma of the
prostate. Eur Urol 1986; 12:441-2.
19. Goluboff ET, McKiernan JM, Todd G, et al. Reconstruction of
urinary and gastrointestinal tracts in total pelvic exenteration: experience at Columbia-Presbyterian Medical Center. Urology 1994;
44:666-70.
20. Mostofi FK, Price EB Jr. Tumours of the male genital system. In:
Firminger HI, eds. Atlas of tumour pathology. Washington DC,
Armed Forces Institute of Pathology, 1973; Second series, Fascicle 8.
21. Young RH, Srigley SR, Amin MB, et al. Tumours of prostate
Correspondence
Gianna Pace, MD
Department of Health Sciences
University of L’Aquila
via San Salvatore 6 A, Coppito - 67100 L’Aquila, Italy
[email protected]
Roberto Pomante, MD
Department of Pathology,
Mazzini Hospital, piazza Italia 1 - 6410 Teramo, Italy
Carlo Vicentini, MD
Department of Urology
Mazzini Hospital, piazza Italia 1 - 6410 Teramo, Italy
[email protected]
108
Archivio Italiano di Urologia e Andrologia 2010; 82, 2
23. Wick MR, Young RH, Malvesta R, et al. Prostatic carcinosarcomas. Clinical, histologic, and immunohistochemical data on two
cases, with a review of the literature. Am J Clin Pathol; 92:131-9.
24. Kelley TW, Borden EC, Goldblum JR. Estrogen and progesterone
receptor expression in uterine and extrauterine leiomyosarcomas: an
immunohistochemical study. Appl Immunohistochem Mol Morphol
2004; 12:338-41.
25. Ren FY, Lu JP, Wang J, et al. Adult prostate sarcoma: radiological-clinical correlation. Clin Radiol 2009; 64:171-7.
26. Ahlering TE, Weintraub P, Skinner DG. Management of adult
sarcomas of the bladder and prostate. J Urol 1988; 140:1397-9.
27. Pisters PW, Ballo MT, Fenstermacher MJ, et al. Phase I trial of
preoperative concurrent doxorubicin and radiation therapy,surgical
resection, and intraoperative electron-beam radiation therapy for
patients with localized retroperitoneal sarcoma. J Clin Oncol 2003;
21:3092-7.
ORIGINAL PAPER
Laparoscopic versus open radical
retropubic prostatectomy:
A case-control study at a single institution.
Francesco Saverio Grossi 1, 2, Sebastiano Di Lena 2, Donato Barnaba 1,
Lorenzo Larocca 1, Michele Raguso 1, Giovanni Sallustio 1, Nicola Raguso 1
1 Division
2 U.S.
Summary
of Urology, Hospital “Valle d’Itria”, Martina Franca (TA), Italy;
of Urology, Hospital of Castellaneta (TA), Italy
We retrospectively compared 50 patients treated with open retropubic prostatectomy
(RRP) with 50 patients treated with laparoscopic extraperitoneal radical prostatectomy
(LRP) at our institution, in the same time period, with a follow-up up to 7 years. We
focused on operative data, complications, pathological outcome and mid-term outcome
and follow-up in terms of oncological results. The same surgeons performed both operations. The 2 groups were similar with respect to mean patient age, mean prostate specific antigen value, median Gleason score. No previous transurethral resection of the prostate nor neoadjuvant treatment, had been undertaken in both groups of pts. Mean operating time was significantly shorter after open surgery (126 minutes, range 90-185 minutes) [p = 0.03] compared to
the laparoscopic group (188 minutes, range 130-250) but it did not differ significantly from the
last 20 laparoscopic procedures, in which the time of procedure was reduced to a mean of 155
minutes group (range 140-184 minutes) [p = 0.1]. Mean blood loss (1,150 versus 800 cc) and
transfusion rates (55.7% versus 19.6%) in the 2 groups significantly favored the laparoscopic
group. Number of lymphnodes dissected during the procedures favoured, but not significantly,
the RRP group: for RRP a mean 11 lymphnodes right side, 13 left side (ranges 2-20 and 2-19
respectively), while for LRP a mean of 9 lymphnodes right side, 11 left side (ranges 2-15 and 213 respectively) were collected. The complication rate was almost the same in both groups, with
no major adverse events nor deaths, (19.2% versus 14.7%) but the spectrum differed. The laparoscopic group had a higher incidence of fever (1.8% versus 3.2% respectively) and subcutaneous
or scrotal emphysema, whereas more lymphoceles (6.9% versus 0%), wound infection (2.3% versus 0.5%), embolism/pneumonia (2.3% versus 0.5%) and anastomotic strictures (15.9% versus
4%) occurred after open surgery. Median catheter time was longer after open retropubic prostatectomy (22 versus 8.9 days, respectively) but the continence rates (intended as complete continence with no use of pads) were similar in both groups at 12 months (90.3% versus 91.7%). The
rate of positive margins did not differ significantly in groups, and was in all cases very low (8.2%
versus 7.0%), prostate specific antigen biochemical recurrence was equivalent (10% vs 10%).
Data regarding postoperative sexual function favoured the laparoscopic group, even if no statistical significance was recorded (55% vs 67%). No statistical differences were observed in terms
of oncological results, with a 24 months mean follow-up. Laparoscopic radical prostatectomy is
technically demanding, with an initially longer operative time and learning curve. The overall
outcome in our series favours the laparoscopic approach regarding catheterization time, recover of continence and impotence , hospital stay, transfusion rate. The open approach is favoured
for the still shorter time necessitating for the procedure. Consequently, at our institution laparoscopic radical prostatectomy is becoming the method of choice.
KEY WORDS: Laparoscopy; Radical prostatectomy; Prostate cancer.
Submitted 24 July 2009; Accepted 30 December 2009
Archivio Italiano di Urologia e Andrologia 2010; 82, 2
109
F.S. Grossi, S. Di Lena, D. Barnaba, L. Larocca, M. Raguso, G. Sallustio, N. Raguso
INTRODUCTION
There is an ongoing debate about the benefits of laparoscopic radical prostatectomy compared to the open
retropubic approach. We retrospectively compared 50
patients treated with open retropubic prostatectomy
(RRP) with 50 patients treated with laparoscopic
extraperitoneal radical prostatectomy (LRP) at our institution, in the same time period, with a follow-up up to 7
years. We focused on operative data, complications,
pathological outcome and mid-term outcome and follow-up in terms of oncological results.
MATERIALS
AND METHODS
A total of 295 patients were treated with open prostatectomy (RRP) and pelvic lymph node dissection while 95
patients underwent LRP with pelvic lymph node dissection in the same time period. From the patients who
underwent a RRP or LRP from December 2002 to
November 2007 we recruited 50 consecutive patients for
each technique to enter this case-control study. To reduce
the bias due to the learning curve in LRP, the first 20 pts
who had had undergone the procedure were not considered, such as the last 25 due to shorter follow-up period.
The same surgeons performed both operations. The 2
groups were similar with respect to mean patient age,
mean prostate specific antigen value, pathological stage,
median Gleason score (Table 1).
No previous transurethral resection of the prostate nor
neoadjuvant treatment, had been undertaken in both
groups of patients.
SURGICAL TECHNIQUES
Open RRP was performed in the usual way, according to
Walsh (1-3) nerve sparing technique. The limphnode
template involved external iliac vessels and obturatorius
fossa. 4 to 6 single stitches in
Polyglicole were used for the
urethrovesical anastomosys,
with an indwelling Foley catheter.
LRP was conducted extraperitoneally, with antegrade
Age years
bladder neck dissection until
PSA (Preop) (ng/ml)
the identification of vas deferens and seminal vesicles.
Gleason Score (Postop)
The template of lymphnode
dissection was the same then in open procedure. The
dorsal complex was secured, for the first 30 procedure,
with Hem-O-Lok system but, due to the migration of the
staples in the bladder, observed in 4 patients several
months after the procedure, the actual technique went
back to a single stitch (0 polyglicole, CT1 needle) passed
after the dissection of the posterior and lateral faces of
the prostate.
Prostatic pedicles and nerve-sparing procedure was, and
still is, carried one with Hem-O-Lok staples, assuring a
very good haemostasis with no use of termal sources.
Urethrovesical anastomosis has been carried out with 2
semicontinous running suture, according to Van
Velthoven (4) technique.
RESULTS
Mean operating time was significantly shorter for open
surgery (126 minutes, range 90-185 minutes) [p = 0.03]
compared to the early laparoscopic group (188 minutes,
range 140-250) but it did not differ significantly from the
last 20 laparoscopic procedures, in which the time of
procedure was reduced to a mean of 155 minutes (range
130-184 minutes) [p = 0.1]. Mean blood loss (1.150 versus 800 cc) and transfusion rates (55.7% versus 19.6%)
in the 2 groups significantly favoured the laparoscopic
group.
Number of lymphnodes dissected during the procedures
favoured, but not significantly, the RRP group: for RRP a
mean 11 lymphnodes right side, 13 left side (ranges 2-20
and 2-19 respectively), while for LRP a mean of 9 lymphnodes right side, 11 left side (ranges 2-15 and 2-13
respectively) were collected (Table 2).
The complication rate was almost the same in both
groups, with no major adverse events nor deaths, (19.2%
versus 14.7%) but the spectrum differed. The laparo-
Table 1.
Patients data.
RRP
LRP
68.3 (52-71)
66.6 (53-70)
6.38 (2.3-21)
5.8 (3-20)
6 (3+3)
6 (3+3)
RRP
LRP
P value
Mean Operating Time (min)
126 (90-185)
188 (140-250)
0.03
Last 20 LRP Op. Time (min)
155 (130-184)
0.1
Blood loss (ml)
1150
800
0.03
Transf.rate
55.7%
19.6%
0.03
Number of LN right
11 (2-20)
9 (2-15)
> 0.5
Number of LN left
13 (2-19)
11 (2-13)
> 0.5
Table 2.
Surgical outcome.
110
Archivio Italiano di Urologia e Andrologia 2010; 82, 2
Laparoscopic versus open radical retropubic prostatectomy: A case-control study at a single institution
Table 3.
Complications.
RRP
LRP
Overall complication rate (%)
19.7
14.7
Fever (%)
1.8
3.2
Subcout./scrotal emphysema (%)
0
15
Lymphoceles (%)
6.9
0
Wound infection (%)
2.3
0.5
Embolism/pneumonia (%)
2.3
0.5
Anastomotic strictures (%)
15.9
4
Migration of Hem-O-lok (%)
0
8
Figure 1.
Kaplan Meier curves for biochemical progression.
Biochemical progression
which the Hem-O-lock system has been
used for haemostasys of the dorsal complex,
a migration of the staples has been observed
in 4 pts (8%), necessitating of late endoscopic removal from the bladder (Table 3).
The amount of postoperative analgesia was
significantly greater after open surgery
(50.8 versus 33.8 mg respectively). Median
catheter time was longer after open retropubic prostatectomy (22 versus 8.9 days,
respectively) but the continence rates
(intended as complete continence with no
use of pads) were similar in both groups at
12 months (90.3% versus 91.7%).
Data regarding postoperative impotentia
coeundi were favouring the laparoscopic
group, even if no statistical significance was
recorded (55% vs 67% of recover after surgery, with early rehabilitation carried out
with oral agents). Actually most of the
patients are satisfied for their sexual life, half
of them still using daily vardenafil 5 mg.
The rate of positive margins did not differ
significantly in groups, and was in all cases
very low (8.2% versus 7.0%), prostate specific antigen biochemical recurrence was
equivalent in the 2 groups (10% vs 10%).
Actually, we had no death resulting from
the progression of prostatic carcinoma
(PCa), and biochemical progression rate,
to date, with a mean follow-up of 38
months (24-84 months, for both groups) is
reported in Figure 1.
DISCUSSION
Since early eighties RRP has become the
procedure of choice for the treatment of
localized PCa. Anatomical studies by Walsh
et al. (1-3) dramatically improved the outcome
of the open procedure in terms of
Table 4.
postoperative recover of continence and
Comparison of KM curves for biochemical progression.
sexual function. Therefore, ameliorating
the procedure by means of reduction of
Endpoint observed n.
6
6
hospital stay, catheterization time, pain
Expected n
6.8
5.2
reduction and return has been the objecChi-square
0.2378
tive surgeons where looking for.
Laparoscopic RP was first performed on a
DF
1
large scale at the beginning of this century
Significance
p = 0.6258
thanks to the standardization of the technique by Vallancien and Guilloneau (6.11,
95% CI
0.2325 to 2.4051
12) that led to a worldwide spread of this
technique. On the other hand LRP is a
challenging procedure that needs a skilled
laparoscopic surgeon and a well trained equipe (13). At
scopic group had a higher incidence of fever (1.8% versus 3.2% respectively) and subcutaneous or scrotal
our institution laparoscopy was began in the mid
emphysema, whereas more lymphoceles (6.9% versus
nineties with incontinence surgery (14) thus developing
0%), wound infections (2.3% versus 0.5%), episodes of
skilness to perform LRP. Analysis of our case-control
embolism/pneumonia (2.3% versus 0.5%) and anastostudy confirms the advantages of of LRP, in respect to
motic strictures (15.9% versus 4%) occurred after open
open RP, almost in all aspects, except for time needed to
surgery.
perform the procedure, that, in any way, tends to reduce
In a small group of patients who underwent LRP and in
with further surgical experience.
Archivio Italiano di Urologia e Andrologia 2010; 82, 2
111
F.S. Grossi, S. Di Lena, D. Barnaba, L. Larocca, M. Raguso, G. Sallustio, N. Raguso
From an oncological point of view it seems also from our
series that no differences can be shown if LRP is performed correctly, following the same principles, in
respect to open surgery (8, 9). Further follow-up may be
needed to confirm these data.
Therefore we can conclude that laparoscopic radical
prostatectomy is technically demanding, with an initially
longer operative time and learning curve. The overall outcome in our series favours the laparoscopic approach
regarding catheterization time, recover of continence and
impotence, hospital stay, transfusion rate. The open
approach is favoured for the still shorter time necessitating
for the procedure. No statistical differences were observed
in terms of oncological results, with a 24 months mean follow-up.
Consequently, at our institution laparoscopic radical
prostatectomy is becoming the method of choice.
5. Tal R, Alphs HH, Krebs P, et al. Erectile function recovery rate
after radical prostatectomy: a meta-analysis. J Sex Med 2009;
6:2538-46.
REFERENCES
11. Guillonneau B, Cathelineau X, Barret E, et al. Laparoscopic radical prostatectomy. Preliminary evaluation after 28 interventions.
Presse Med 1998; 27:1570-4.
1. Reiner WG, Walsh PC. An anatomical approach to the surgical
management of the dorsal vein and Santorini's plexus during radical retropubic surgery. J Urol 1979; 121:198-200.
2. Walsh PC, Jewett HJ. Radical surgery for prostatic cancer. Cancer
1980; 45(7 Suppl):1906-11.
7. Levinson AW, Su LM. Laparoscopic radical prostatectomy: current
techniques. Curr Opin Urol 2007; 17:98-103.
8. Rassweiler J. Open vs. laparoscopic radical prostatectomy... and
laparoscopy is better! Eur Urol 2006; 50:26-8.
9. Guazzoni G, Cestari A, Naspro R, et al. Intra- and peri-operative
outcomes comparing radical retropubic and laparoscopic radical
prostatectomy: results from a prospective, randomised, single-surgeon study. Eur Urol 2006; 50:98-104.
10. Klän R, Dieckmann KP, Meier T, et al. Laparoscopic vs. open
surgical lymphadenectomy in prostate cancer. Methodological comparison Urologe A 1994; 33:128-32.
12. Guillonneau B, Vallancien G. Laparoscopic radical prostatectomy: the Montsouris technique. J Urol 2000; 163:1643-9.
3. Walsh PC. Radical prostatectomy for the treatment of localized
prostatic carcinoma.Urol Clin North Am 1980; 7:583-91.
13. Vickers AJ, Savage CJ, Hruza M, et al. The surgical learning
curve for laparoscopic radical prostatectomy: a retrospective cohort
study. Lancet Oncol 2009; 10:475-80.
4. Van Velthoven RF, Ahlering TE, Peltier AS, et al. Technique for
laparoscopic running urethrovesical anastomosis:the single knot
method. Urology 2003; 61:699-702.
14. D’Elia A, Grossi FS, Larocca L, et al. Colposospension: Burch
technique in extrapeitoneal laparoscopy. Acta Urol Ital 1998;
12:255-258.
Correspondence
Francesco Saverio Grossi, MD
Division of Urology - Hospital “Valle d’Itria”
P.zza S. Francesco Da Paola, 1 - 74015 Martina Franca (TA), Italy
[email protected]
Di Lena Sebastiano, MD
U.S. of Urology Castellaneta Hospital
Castellaneta - Taranto, Italy
Barnaba Donato, MD
Division of Urology - Hospital “Valle d’Itria”
P.zza S. Francesco Da Paola 1 - 74015 Martina Franca (TA), Italy
Larocca Lorenzo, MD
Division of Urology - Hospital “Valle d’Itria”
P.zza S. Francesco Da Paola 1 - 74015 Martina Franca (TA), Italy
Raguso Michele, MD
Division of Urology - Hospital “Valle d’Itria”
P.zza S. Francesco Da Paola 1 - 74015 Martina Franca (TA), Italy
Sallustio Giovanni, MD
Division of Urology - Hospital “Valle d’Itria”
P.zza S. Francesco Da Paola 1 - 74015 Martina Franca (TA), Italy
Raguso Nicola, MD
Director
Division of Urology - Hospital “Valle d’Itria”
P.zza S. Francesco Da Paola 1 - 74015 Martina Franca (TA), Italy
112
6. Romero-Otero J, Touijer K, Guillonneau B. Laparoscopic radical
prostatectomy: contemporary comparison with open surgery.Urol
Oncol 2007; 25:499-504.
Archivio Italiano di Urologia e Andrologia 2010; 82, 2
CASE REPORT
Ureteral injury concomitant
with kidney injury due to blunt trauma: Case report.
Murad G. Asali, Igor Romanowsky, Jacob Kaneti
Urology Department, Ben Gurion University, Soroka Medical Center, Beer-Sheva, Israel
Summary
A 27- year old man fell from seven meters high. A CT of abdomen and pelvis with contrast injection showed injury of right kidney, perirenal hematoma, and periureteral
extravasation of contrast. Retrograde pyelography confirmed the diagnosis of partial
transection of the right upper ureter. Conservative management of the case is discussed. A JJ internal ureteral stent was inserted successfully.
KEY WORDS: Ureteral injury; Blunt trauma; Stent; Renal injury.
Submitted 30 November 2008; 15 January 2009
INTRODUCTION
Traumatic ureteral injuries are less than 1% of all genitourinary injuries from external violence. Only 2% to 3%
of gunshot wounds to the abdomen result in ureteral
injury (1, 2). Blunt trauma is rarely causative and constitutes only 3.5% of traumatic ureteral injuries.
Penetrating trauma is the cause of remaining 96.5% (3).
Noniatrogenic ureteral injuries are uncommon because
the ureter is well protected anatomically by the bony
pelvis and psoas muscle. Thus, injuries to the ureters are
associated with major organ injury (3). Iatrogenic ureteral injuries occurring in up to 1.1% of hysterectomies and
in up to 4.7% of ureteroscopies (4).
CASE
der X- Ray scan showed multiple injuries of right kidney
grade 4, perirenal hematoma, and periureteral extravasation of contrast (Figure 1, Figure 2). The patient was
taken to the operating room and retrograde pyelography
confirmed the diagnosis of partial transection of the right
upper ureter close to ureteropelvic junction and extravaFigure 1.
CT of abdomen with contrast injection shows major
right renal injury, perirenal hematoma (white arrow),
and periureteral extravasation of contrast (black arrow).
PRESENTATION
A 27-year old man was admitted after he had fallen from
seven meters high. At admission he was alert, spontaneously breathing, Blood pressure was 120/70 mm Hg,
and heart rate (HR) 70 bpm. Cardiopulmonary examination was normal. There was tenderness on the right
upper abdomen, tenderness on the right flank without
hematomas, swelling and tenderness on the right elbow.
Genitalia and digital rectal examination were normal.
Laboratory evaluation demonstrated: Haemoglobin
(Hb)13.1 g/dl, Hematocrit (Ht) 40%, White blood count
(WBC) 20280/ul, platlets (PLT) 261000/ul, Serum Urea
34 mg/dl, Serum Creatinine 1.12 mg/dl. Urine examination showed microhematuria. Chest and pelvis X-Ray
were normal. There were fractures of right radius and
ulna. Computed Tomography (CT) of abdomen and
pelvis with contrast injection and a kidney ureter bladArchivio Italiano di Urologia e Andrologia 2010; 82, 2
113
Murad G. Asali, I. Romanowsky, J. Kaneti
Figure 2.
KUB some minutes post the abdominal CT scan
which shows contrast extravasation of the right
upper ureter before internal stent insertion.
Figure 4.
Intravenus pyelography twelve weeks post the injury
after the ureteral stent was removed. There was no
obstruction and no extravasation of contrast medium.
Figure 3.
Post ureteral stent insertion with the extravasation
of contrast medium adjacent to the upper ureter.
admission there was a drop of Hb to 7.6 g/dl and four
packed cell units were given. Hb rose to 12.2 g/dl.
Another CT of abdomen with intravenous contrast injection revealed large right perirenal hematoma, stent in
normal position, and normal left kidney. Twelve days
after the admission the patient was operated by the
orthopedic team because of the fractures of right radius
and ulna.
Three weeks after the admission the patient was discharged and eight weeks later the ureteral stent was
removed. In retrograde pyelography a minimal irregularity of the right upper ureter without obstruction and no
extravasation of contrast medium was revealed.
Intravenous pyelography (IVP) 3 months after the trauma showed no obstruction or ureteral stricture (Figure 4). The patient has not had any problems for 21
months of follow up.
DISCUSSION
sation from the lower pole of the kidney. A JJ stent 6 Fr
was inserted successfully (Figure 3).
The patient was followed with bed rest, physical examination, complete blood count, renal function, electrolytes every day, and antibiotics. Two days post the
114
Archivio Italiano di Urologia e Andrologia 2010; 82, 2
Blunt ureteral injury is rare, most of the injuries were published as case reports (5-10). Bilateral ureteral rupture is
extremely rare (6). Best et al reported 57 ureteral injuries
in a 120 months study in which the mechanism of injury
was penetrating in 96.5% and blunt in only 2 (3.5%) (11).
Elliot and McAninch reported their 25 year experience
with 38 traumatic ureteral injuries, blunt trauma was the
cause in 5 patients (3). Avulsion of the ureteropelvic junction is by far the most common ureteral injury in children,
usually occurring in those involved in motor vehicle acci-
Ureteral injury concomitant with kidney injury due to blunt trauma: Case report
dents or in falls from a height (12-14). Complete rupture
occurs mostly 1 to 2 cm below the ureteropelvic junction,
whereas only a few sites of rupture at a greater distance
from the renal pelvis have been reported. Laceration without complete avulsion is far less common and predominantly involves adults (7, 14).
Diagnosis of the ureteral injuries can be difficult.
Hematuria, which is the most consistent finding in renal
trauma, is absent in approximately 30% of ureteral injuries.
Fever, flank pain, expanding flank mass, urinoma and
fistula formation, and sepsis usually confirm late diagnosis (3, 7, 13, 14). CT scan is the gold standard for staging of blunt abdominal and genitourinary trauma.
For the diagnosis of renal injury contrast enhanced CT
with delayed scans and pyelography are indicated in all
patients with blunt injury with macrohematuria, microhematuria with hypotension, or rapid deceleration
injuries. A similar protocol can be used for ureteral
injuries. Many ureteral injuries will be missed if hematuria and hypotension are absent (3). Best et al reported
hematuria only in 17% of their 57 patients with ureteral
injuries (11).
Therefore, to improve the detection of ureteral injuries
the index of suspicion should increase to include imaging in patients with flank ecchymosis, tenderness or
rapid deceleration trauma. CT is better than Intravenous
pyelography (IVP) for the diagnosis of ureteral and associated injuries. IVP was positive in 65% in confirmed
traumatic ureteral injuries (3).
In our case we decided to start with internal drainage
and stenting instead of open exploration, repairing the
renal injuries, debridement, and watertight tension free
ureteroureteral anastomosis.
In conclusion, blunt ureteral injury requires a high index
of clinical suspicion to establish the diagnosis. Contrast
enhanced CT with delayed scans can help in the diagnosis. Conservative treatment with double J internal stent
can be successful for patients with combined blunt renal
and ureteral injury.
REFERENCES
1. Azimuddin K, Milanesa D, Ivatury R, Porter J, Ehrenpreis M,
Allman DB. Penetrating ureteric injuries. Injury 1998; 29:363.
2. Presti JC, Carroll PR, McAninch JW. Ureteral and renal pelvic
injuries from external trauma: diagnosis and management. J
Trauma 1989; 29:370.
3. Elliott SP, McAninch JW. Ureteral injuries from external violence:
The 25- year experience at San Francisco General Hospital. J Urol
2003; 170:1213-1216.
4. Schuster TG, Hollenbeck BK, Faerber GJ, Wolf JS. Complications
of ureteroscopy: analysis of predictive factors. J Urol 2001; 166:538.
5. Whitesides E, Kozlowski DL. Ureteral injury from blunt abdominal trauma: case report. J Trauma 1994; 36:745-6.
6. Grunert K, Goritz E, Eisenberger F. Bilateral ureteral rupture in
a child after blunt trauma. Urologe A 1994; 33:487-9.
7. Pumberger W, Stoll E, Metz S. Ureteropelvic junction disruption
following blunt abdominal trauma. Pediatr Emerg Care 2002;
18:364-366.
8. Gunnarsson U, Lewenhaupt A, Heuman R. Ureteral wound
caused by blunt abdominal trauma. Scand J Urol Nephrol 2003;
37:88-9.
9. Maruyama E, Azuma H, Kiyama S, et al. Complete avulsion of
ureter caused by abdominal blunt injury: a case report. Hinyokika
Kiyo 2004; 50:187-90.
10. Toporoff B, Scalea TM, Abramson D, Scalafani SJ. Ureteral laceration caused by a fall from a height: case report and review of the
literature. J Trauma 1993; 34:164-6.
11. Best CD, Petrone P, Buscarini M, et al. Traumatic ureteral
injuries: a single institution experience validating the American
Association for the Surgery ofTrauma-Organ Injury Scale grading
scale. J Urol 2005; 173:1202-5.
12. Reznichek RC, Brosman SA, Rhodes DB. Ureteral avulsion from
blunt trauma. J Urol 1973; 109:812-6.
13. Laberge I, Homsy YL, Dadour G, Beland G. Avulsion of ureter
by blunt trauma. Urology 1979; 13:172-8.
14. Palmer JM, Drago JR. Ureteral avulsion from non-penetrating
trauma. J Urol 1981; 125:108-11.
Correspondence
Asali Murad, MD
Urology Department, Ben Gurion University
P.O.B 151, Soroka Medical Center
84101 Beer-Sheva, Israel
[email protected]
Igor Romanowsky, MD
Urology Department - Ben Gurion University
P.O.B 151, Soroka Medical Center
84101 Beer-Sheva, Israel
[email protected]
Jacob Kaneti, MD
Professor
Urology Department - Ben Gurion University
P.O.B 151, Soroka Medical Center
84101 Beer-Sheva, Israel
[email protected]
Archivio Italiano di Urologia e Andrologia 2010; 82, 2
115
CASE REPORT
Thirty years old man
with a huge benign prostatic enlargement.
Pavlos Gkritsios, Asterios Fotas, Michael Bekas, Vasilis Adamou, Vasileios Katsikas
2nd University Department of Urology, “Papageorgiou” Hospital, Thessaloniki, Greece
Summary
We present a case of a thirty years old man who had suprapubic prostatectomy in our
department. Patient’s history started from the age of 25, when he experienced multiple urinary retention attacks. Imaging revealed an enormous prostatic mass.
Combining this finding with elevated PSA values, lead us to prostatic biopsies which
proved to be benign. Following our advice, the patient had children and afterwards he
had his prostate removed. The suprapubic prostatectomy was extremely challenging with a lot
of technical difficulties, considering that the net weight of the removed adenoma was 250gr.
Pathological examination of the tissue proved that it was benign prostatic hyperplasia.
Our case is particularly interesting for two reasons: On one hand because of the unusual size
of the prostate and on the other hand because of the young age of the patient. Epidemiological
studies showed that prostatic hyperplasia has been pathologically proved only after the age of
40, while pathological signs of the disease could be found after the age of 30. Concerning the
size of the adenoma, a search in the literature showed that only 4% of the removed glands
weight more than 100 gr, and that has to do with men over 70 years of age. Concluding, our
case seems to be extremely rare. Furthermore, our search through the literature could not
reveal any similar case report.
KEY WORDS: Prostatic adenoma; Benign prostatic hyperplasia; Prostatectomy.
Submitted 2 April 2009; Accepted 30 June 2009
CASE
REPORT
A thirty years old male was referred to our clinic because
of recurrent urinary retention episodes and severe LUTS.
His first urinary retention had occurred five years before
(at the age of 25) when he had a knee surgery. Another
couple of retention episodes took place up until three
years before when LUTS had started. He complained for
nocturia (1-2 times), frequency and dysuria. During the
last three years, the frequency of retention had become
higher, taking place every two to three months. Retention
occurred after he had to postpone micturition or after
consuming alcohol.
DRE revealed a huge prostate with edges that could not
be reached to palpation. Normal prostatic texture was
palpated with no hard nodules or any signs of malignancy. The patient’s uroflowmetry had an obstructed pattern.
Ultrasonography, CT scan, MRI, showed a very large,
heterogeneous, well defined prostatic mass, 300ml in
volume (Figure 1, 2, 3). PSA was 43, while hormonal
profile of the patient was normal.
A needle biopsy was performed. 17 cores were examined
and no sign of malignancy was found. BPH was the
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Archivio Italiano di Urologia e Andrologia 2010; 82, 2
Figure 1.
Ultrasound image of the adenoma.
pathology diagnosis. Because of the recurrent urinary
retention episodes and after a-blockers and finasteride
have failed, surgery has been advised. Taking in mind the
Thirty years old man with a huge benign prostatic enlargement
risk of retrograde ejaculation, the patient postponed the surgery for
two years and had two
children.
Finally we performed an
open suprapubic prostatectomy. The operation
was extremely challenging. No post operative
complications occurred
and the patient had the
catheter removed 8 days
after surgery.
Pathology examination
of the specimen measured a 250 gr prostatic
adenoma (Figure 4) with
12 x 11 x 8 cm dimensions. The diagnosis was
BPH again. Microscopic
examination showed prevalence of glandular over
stromal hyperplasia.
Figure 2.
CT scan.
Figure 3.
MRI.
DISCUSSION
The natural history and
development of BPH with
age has always been an
enigma for Urologists. A
survey of the literature on
the growth of human
prostate and prevalence of
histological recognizable
benign prostatic hyperplasia identified 23 independFigure 4.
ent studies (1-23). These
The prostatic adenoma specimen.
studies proved that normal prostate increases in
size in association with
age. The growth of most
human prostates can be
divided into rapid (subjects between 0 and 30
years old) and slow (men
between 31 and > 90 years
old) phases.
However, 3.7% of the
prostates in men > 70
years old attain a large
weight (> 100 gr) (24).
Analyzing 10 autopsy
and prostatectomy studies, Berry et al. concludes
that the first pathological sign of benign prostatic hypersmall doubling time of the human tumor the first
plasia is seen in men between 31 and 40 years old but
appearance of a pathological nodule would not be noted
the prevalence is only 8%.
for an additional 10 to 20 years.”
The amount of hyperplastic tissue removed at surgery
Concerning the development of BPH with age Oesterling
increases with advancing age and the same review article
agrees that the initial development of BPH begins as early
Berry et al. concludes that “the initiation of growth of
as 25 to 30 years of age. Furthermore, the time required
BPH probably begins in men < 30 years old. With the
for macroscopic BPH to develop from microscopic BPH
Archivio Italiano di Urologia e Andrologia 2010; 82, 2
117
P. Gkritsios, A. Fotas, M. Bekas, V. Adamou, V. Katsikas
is approximately 5 years. The age specific prevalence of
macroscopic BPH, as detected by DRE, increases with
age. Concerning the large prostates, Oesterling found
that among men who were older than 70 years, 3.5%
had a prostate that weighted more than 100 gr. (25)
According to these studies, macroscopic BPH could not
be found earlier than the age of 30. On the contrary, our
case presents a huge prostatic enlargement found and
digitally palpated on a 28 years old man.
At the age of 30 our patient had prostatectomy and the
specimen weighted 250 gr. This size of prostate is very
rare even between men > 70 years old.
The meticulous examination of the specimen proved
only typical BPH pathology. Taking also in mind that the
patient had no other diseases, no family history and his
hormonal status was normal, BPH is the only clinical
diagnosis that could be made for this young man.
As a conclusion, our case is extremely rare for two reasons: first because of the young age of the patient, and
the second because of the very large size of the
prostate. No similar case could be found through the
literature.
REFERENCES
1. Swyer GIM. Post natal growth changes in the human prostate. J
Anat 1994; 78:130.
16. Ashley DJ. Observations on the epidemiology of prostatic hyperplasia in Wales. Brit. J Urol 1966; 38:567.
17. Lytton B, Emery JM, Harvard BM. The incidence of benign prostatic obstruction. J Urol1968; 99:639.
18. Harbitz TB, Haugen OA. History of the prostate in elderly men.
A study in an autopsy series. Acta Path. Microbiol Scand [A], 1972;
80:756.
19. Haugen OA, Harbitz TB. Prostatic weight in elderly men. An
analysis in an autopsy series. Acta Path. Microbiol Scand [A], 1972;
80:769.
20. Pradhan BK, Chandra K. Morphogenesis of nodular hyperplasic- prostate J Urol 1975; 113:210.
21. Leissner KH, Tissel LE. The weight of the human prostate.
Scand. J Urol Nephrol 1979; 13:137.
22. Leissner KH, Tissel LE. The weight of the dorsal, lateral and
medial prostatic lobes in man. Scand. J Urol Nephrol 1979; 13:223.
23. Birkhoff JD. Natural history of benign prostatic hypertrophy.
Edited by F. Hinman, Jr. and S. Boyarsky. New York: Springer Verlag, chapt. 1, 1983; p. 5.
24. Berry SJ, Coffey DS, Walsh PC, Ewing LL. The development of
human benign prostatic hyperplasia with age. J Urol 1984;
132:474-479.
25. Oesterling JE. The origin and development of benign prostatic
hyperplasia. An age dependent process. J Androl 1991; 12:348-355.
2. Lowsley OS. The development of the human prostate gland with
reference to the development to other structures at the neck of the
urinary bladder. Amer. J Anat 1912; 13:299.
3. Lowsley OS. The gross anatomy of the human prostate gland and
contiguous structures. Surg Gynec And Obst 1915; 20:183.
4. Lowsley OS. The human prostate gland in youth. Med Rec 1915;
88:383.
5. Lowsley OS. The prostate gland in old age. Ann Surg 1915; 62:716
6. Lowsley OS. The human prostate gland in middle age. Med Rec
1916; 89:3.
7. Walker KM. Nature and cause of old age enlargement of the
prostate. Brit Med J 1922; 1:297.
8. Gover M. A statistical study of the etiology of benign hypertrophy
of the prostate gland. Johns Hopkins Hosp Rep 1923; 21:231.
9. Hunt, VC. Benign prostatic hypertrophy: a review of 1000 cases.
Surg Gynec And Obst 1928; 46:769.
10. Randall A. Surgical pathology of prostatic obstruction.
Baltimore: The Williams and Wilkins Co., 1931.
11. Teem MVB. The relation of the interstitial cells of the testis to
prostatic hypertrophy. J Urol 1935; 34:692.
12. Moore RA. Benign hypertrophy of the prostate. A morphological
study. J Urol 1943; 50:680.
13. Moore RA. Benign hypertrophy and carcinoma of the prostate:
occurrence and experimental production in animals. Surgery 1944;
16:152.
14. Tornblom N. Contribution to the discussion on etiology of prostatic hypertrophy in man. I. The weight of the prostate and seminal
vesicles in men of different ages. Acta Med Scand 1946; suppl.170:1.
15. Frankw LM. Benign nodular hyperplasia of the prostate: a
review. Ann Roy Coll Surg 1954; 14:92.
118
Archivio Italiano di Urologia e Andrologia 2010; 82, 2
Correspondence
Gkritsios Pavlos
2nd University Department of Urology
“Papageorgiou” Hospital, Thessaloniki, Greece
[email protected]
Asterios Fotas, MD
2nd University Department of Urology
“Papageorgiou” Hospital, Thessaloniki, Greece
Michael Bekas, MD
2nd University Department of Urology
“Papageorgiou” Hospital, Thessaloniki, Greece
V. Adamou, MD
2nd University Department of Urology
“Papageorgiou” Hospital, Thessaloniki, Greece
V. Katsikas, MD
2nd University Department of Urology
“Papageorgiou” Hospital, Thessaloniki, Greece
CASE REPORT
Metastasis to the renal hilum from
malignant melanoma of the anterior trunk:
An unusual finding.
Francesco Pinto 1, Emanuele Cappa 1, Antonio Brescia 1,
Emilio Sacco 1, Andrea Volpe 1, Angelo Totaro 1, Mario Gardi 1,
Francesco Pierconti 2, Pier Francesco Bassi 1
1
2
Summary
Department of Urology, Catholic University School of Medicine, Rome, Italy;
Department of Histopathology, Catholic University School of Medicine, Rome, Italy
A retroperitoneal metastasis from malignant melanoma is an uncommon event and mostly secondary to a primary lesion of the posterior trunk. We report on a 38-year-old
patient with malignant melanoma of the anterior trunk who presented a symptomatic
metastatic mass of the left renal hilum not originating from the retroperitoneal lymph
nodes of the renal hilum, surrounding and infiltrating the renal pelvis, treated with left
nephrectomy, complete mass excision and regional lymph node dissection. The patient later developed also brain metastases and is now undergoing immunotherapy.
KEY WORDS: Skin melanoma; Metastasis; Retroperitoneum; Lymphatic drainage.
Received 19 October 2009; Accepted 23 April 2010
INTRODUCTION
Clinically evident metastatic melanoma to the retroperitoneum is an uncommon event. Up to 50% of patients
with a history of melanoma have multiple renal sub cortical micro metastases on autopsy (1). A review of the
published papers showed several previous cases of solitary metastatic melanoma renal lesions (2) but only few
reports were published about retroperitoneal metastasis
from melanoma of the posterior trunk (3-4).
We report the case of a metastasis from malignant
melanoma of the anterior trunk surrounding the left
renal pelvis not originating from the retroperitoneal
lymph nodes of the renal hilum. To Our knowledge, the
location of this metastastatic disease has never been previously described.
CASE REPORT
A 38-year-old man first presented a malignant melanoma
of the anterior trunk in the sternal area in August 2006.
The patient underwent a wide local excision with an
overdraw resection after 2 months. In December 2006 he
underwent the left sentinel axillaries lymph node dissection that resulted positive for metastatic melanoma at
histopathological examination. Subsequently, the patient
underwent immunotherapy with interferon-alfa.
In December 2007 he underwent a new left axillaries
lymph node dissection for a positive PET-TC but the
histopathological examination was negative for metastatic melanoma.
In February 2008 the patient presented left lumbar pain,
fever, without hematuria. The physical examination findings were unremarkable. The laboratory data from the
blood and urine samples were within normal limits
except for a mild anaemia. Urinary cytology was negative
for neoplastic cells.
The radiologic workup with computed tomography (CT)
disclosed a solid-inhomogeneous mass of 3 x 6 cm that
completely filled the left renal hilum and partially
occluded the renal pelvis. It determined an increase of
density of the adipose perirenal tissue that catch up the
wrap renal front (Figure 1).
Subsequently, the patient underwent left nephrectomy,
complete excision of the mass surrounding the renal
pelvis and a local lymph node dissection through a lombotomic approach. The surgeon described the presence
of a neoformed solid weaving that encircled and seemed
to infiltrate the left renal pelvis reaching the parietal peritoneum.
The patient’s postoperative course was uncomplicated
and he was discharged home on postoperative day 5.
The final pathologic examination demonstrated a 6 cm
tumour, occupying the renal hilum. The mass was
Archivio Italiano di Urologia e Andrologia 2010; 82, 2
119
F. Pinto, E. Cappa, A. Brescia, E. Sacco, A. Volpe, A. Totaro, M. Gardi, F. Pierconti, P.F. Bassi
Immunohistochemical staining with positive
melanoma antigen recognized by S-100, Melan-A,
HMB-45 and negative for cytokeratin, confirmed
the diagnosis of malignant melanoma (Figure 3).
The surgical margins were negative. The tumor did
not show characteristics that could lead back to a
lymph node origin and, moreover, the ilar lymph
nodes dissected were all free of tumor.
At three months follow-up, radiologic evaluation
showed brain tumor metastases and the patient is
now undergoing a new course of immunotherapy.
COMMENT
We report a case of a metastasis from a malignant
melanoma of the anterior trunk involving the left
renal hilum, surrounding the renal pelvis not originating from the retroperitoneal lymph nodes of the
renal hilum.
Melanoma with any visceral metastasis confers a
poor prognosis: 1-year and 2-year survival are
approximately 50% and 25% respectively (5). The
optimal treatment for melanoma is surgical resecFigure 1.
tion. Many adjuvant therapies are available, including immunotherapy such as interferon-alpha and
Abdominal computed tomography (CT) showing a solid mass
IL-2 and chemotherapy such as dacarbazine and
that completely filled the left renal hilum
fotemustine (6).
and partially occluded the renal pelvis.
Immunotherapy and/or chemotherapy are the current treatment options for melanoma with
retroperitoneal lesions or unresectable lesions.
Retroperitoneal metastases of malignant melanoma
are rare findings. Abeshouse et al. reviewed 142
cases of melanoma in the genitourinary tract,
including 56 primary and 86 secondary
melanomas. Eighty percent of melanoma metastases to the kidney had the primary lesion arising
from the skin (7).
Uren et al. observed many unusual lymphatic
drainages pathways, including direct drainage
through the body wall to retroperitoneal and paravertebral lymph nodes from the skin of the
back (3). The Author found this type of lymphatic
drainage occuring in 14 out of 542 patients (3).
Subsequently, Roger et al. demostrated that only
lymphatic drainage for malignant melanomas of the
posterior trunk can involve a direct passage
through the posterior body wall into paravertebral,
Figure 2.
para-aortic or retroperitoneal areas, while
Macroscopic appearance of the tumor
melanomas of anterior trunk metastasize to axillarencompassing the renal hilum.
ies nodes, clavicle or neck nodes using lymphatic
drainage (4).
From a review of the literature, to Our knowledge,
multinodular and heterogeneously pigmented (Figuthe location of this metastastatic disease has never been
re 2). Microscopic examination showed an ilar tumour
previously described. The presented case is a peculiar
that appeared to involve the peri-ilar adipose woven, the
metastasis of the renal hilum from an anterior trunk
ureteral wall, the renal parenchyma and the pelvic wall
malignant melanoma that is hardly explainable by the
with involvement in such zone of the muscular woven
lymphatic drainage pathways widely described (3, 4)
and the connecting tissue but with partial conservation
also because of the absence of histopathological features
of the transitional tissue. The tumour showed a pattern
distinctive of a lymph node origin and the presence of
of solid growth and alveolar, with cancer elements with
multiple ilar lymph nodes dissected free of tumor.
pleomorf nuclei, constantly nucleated, and eosinophils
A review of the literature demonstrated that metastasecthat sometimes included a large cytoplasm.
tomy followed by a new adjuvant treatment is now the
120
Archivio Italiano di Urologia e Andrologia 2010; 82, 2
Metastasis to the renal hilum from malignant melanoma of the anterior trunk: An unusual finding
6. Rosenberg S, Yang JC, Topalian SL et al. Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer
using high-dose bolus interleukin 2. JAMA 1994; 271:907-13.
7. Abeshause BS. Primary and secondary melanoma of the genitourinary tract. South Med J 1958; 51:994-1005.
8. David WO. Complete metastasectomy in patients with stage IV
metastatic melanoma. Lancet Oncol 2006; 7:919-24.
9. Morton DL, Mozzillo N, Thompson JF et al. An International
randomized, double-blind, phase 3 study of specific active
immunotherapy agent, onamelatucel-L (Canvxib), compared to
placebo as a post-surgical adjuvant in AJCC stage IV melanoma:
plenary talk. Society of Surgical Oncology Cancer Symposium, 59
Annual Meeting; March 24, 2006; San Diego, CA, USA.
th
Figure 3.
Microscopic appearance (original magnification x 400)
of the tumor: Immunohistochemical staining for MELAN-A.
ideal therapeutic approach for patients with singular or
multiple distant metastases of melanoma (stage IV) and
it can extend 5-year survival (8). Morton et al. showed
with an international randomized, double-bind, phase 3
study, that the best therapeutic approach for patients
with stage IV disease is not systemic chemotherapy or
biological treatments but rather a complete metastasectomy if technically feasible (9).
In Our case the unusual and single localization of the
mass at diagnosis could appear suspicious for a primary
tumour. A percutaneus biopsy might be warranted to
evaluate cases of suspected secondary metastatic lesions
but in Our case resulted technically difficult for the
tumor location in the renal hilum. Moreover, the results
of a biopsy would not have affected the decision for
nefrectomy because the patient was symptomatic, the
mass was solitary and the brain metastases were not evident when the retroperitoneal mass was diagnosed.
REFERENCES
1. Stein B, Kendall A. Malignant melanoma of the genitourinary
tract. J Urol 1984; 132:859-68.
2. Shimko MS, Jacobs SC, Phelan MW. Renal metastasis of
malignant melanoma with unknown primary Urology 2007;
69:384.e9-10.
3. Uren RF, Howman-Giles R, Thompson JF. Lymphatic drainage
from the skin of the back to retroperitoneal and paravertebral lymph
nodes in melanoma patients. Ann Surg Oncol 1998; 5:384-7.
Correspondence
Francesco Pinto, MD
Department of Urology - Catholic University School of Medicine
Policlinico A. Gemelli, L.go Francesco Vito 1 - 00168 Rome, Italy
[email protected]
Emanuele Cappa, MD
Department of Urology - Catholic University School of Medicine
Policlinico A. Gemelli, L.go Francesco Vito 1 - 00168 Rome, Italy
Antonio Brescia, MD
Department of Urology - Catholic University School of Medicine
Policlinico A. Gemelli, L.go Francesco Vito 1 - 00168 Rome, Italy
Emilio Sacco, MD
Department of Urology - Catholic University School of Medicine
Policlinico A. Gemelli, L.go Francesco Vito 1 - 00168 Rome, Italy
Andrea Volpe, MD
Department of Urology - Catholic University School of Medicine
Policlinico A. Gemelli, L.go Francesco Vito 1 - 00168 Rome, Italy
Angelo Totaro, MD
Department of Urology - Catholic University School of Medicine
Policlinico A. Gemelli, L.go Francesco Vito 1 - 00168 Rome, Italy
Mario Gardi, MD
Department of Urology - Catholic University School of Medicine
Policlinico A. Gemelli, L.go Francesco Vito 1 - 00168 Rome, Italy
4. Uren RF, Howman–Giles R, Thompson JF. Patterns of lymphatic
drainage from the skin in Patients with Melanoma. J Nuclear
Medicine 2003; 44:570-82.
Francesco Pierconti, MD
Department of Histopathology - Catholic University School of Medicine
Policlinico A. Gemelli, L.go Francesco Vito 1 - 00168 Rome, Italy
5. Balch C, Buzaid AC, Soong SJ et al. Prognostic factors analysis of
17.600 melanoma patients: validation of the American Joint
Committee on Cancer melanoma staging system. J Clin Oncol 2001;
19:3622-34.
Pier Francesco Bassi, MD
Professor of Urology
Department of Urology - Catholic University School of Medicine
Policlinico A. Gemelli, L.go Francesco Vito 1 - 00168 Rome, Italy
Archivio Italiano di Urologia e Andrologia 2010; 82, 2
121
ORIGINAL PAPER
Interstitial cystitis with plasma cell bladder infiltration:
Case report and literature review.
Mauro Pacella 1, Virginia Varca 1, Fabio Venzano 1, Carlo Toncini 2,
Giorgio Carmignani 1, Alchiede Simonato 1
1
2
Summary
“Luciano Giuliani” Department of Urology, University of Genoa, Genoa, Italy;
Pathology Department San Martino’s Hospital
We report the case of a 76ys-old woman with overactive bladder syndrome, determined by an histological exam of interstitial cystitis with plasma cell infiltration. To
the best of our knowledge, in literature only a similar case has been described. The
patient has been treated with corticosteroid therapy allowing a transitory benefit;
despite this fact, after side effects have been shown, this therapy has been interrupted
leading to the worsening of the previous sintomatology. Therefore the patient has undergone to
radical cystectomy with orthotopic ileal neobladder. The phlogistic infiltration of the bladder
wall is represented by the plasma cells for over 90% of the whole population. In addition, blood
specimen was positive for perinuclear antineutrophil cytoplasmic antibodies (p-ANCA). All
these elements could hint at a chronic cystitis due to autoimmune aetiology.
KEY WORDS: Plasma cell; Interstitial cystitis.
Submitted 23 February 2009; Accepted 20 April 2009
INTRODUCTION
The presence of plasma cells in the bladder mucosa is
frequent and observable in anatomo-pathological specimens of patients with any kind of chronic cystitis. We
report the case of a patient with severe low urinary tract
symptoms due to a chronic cystitis with massive plasmacells infiltration in the bladder mucosa.
Even if the patient showed clinical and pathologycal evidences in agreement with interstitial and eosinophilic
cystitis, anatomo-patological response of a predominant
plasmacellular infiltration of the bladder suggested a
very rare nosological entity, described in literature only
once so far (1).
CASE
REPORT
A 76ys-old woman showed an overactive bladder syndrome getting worse and worse. The patient had been
previously hit by two episodes of bacteric cystitis. After
the second episode of cystitis, the storage symptoms only
partially regressed, worsening again in the following
weeks, despite the urine culture was negative.
Physical examination was negative. A cystoscopy showed
a spread oedema of the bladder mucosa with a lot of fibrin in suspension. A biopsy of bladder mucosal revealed
inflammation characterized by plasma cells infiltration
which interested the deep layers of corion.
After that it was performed a systematic cold cup histologic mapping under general anaesthesia and the histo-
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Archivio Italiano di Urologia e Andrologia 2010; 82, 2
logical report confirmed the previously diagnosis with
massive plasmacells infiltration of the bladder mucosa
(Figure 1).
Figure 1.
Flexible cystoscopy: The mucosal surface of the bladder
is diffusely edematous and erythematous.
Interstitial cystitis with plasma cell bladder infiltration: Case report and literature review
No antinuclear antibodies were found in the blood while
widely positive for p-ANCA. The citofluorometry determination of the lymphocytic under populations in the
peripheral blood did not highlight significant alterations.
The cytofluorometric immunophenotypical analysis on
the urine leucocytes revealed a notable presence of
CD13+ and CD16+ leucocytes. The plasma levels of Cprotein and of beta 2 microglobulin turned out respectively increased by 30% and by 10% regarding the normal range. All the other inspections were normal.
She was given an oral therapy with Prednisone 25 mg/die
for 15 days and a progressive reduction of the dosage for
a month until 5 mg/die open-ended, with a weekly single dose of Fosfomycin (2-4). The urinary symptoms significantly decreased after two weeks from the beginning
of the corticosteroid therapy with almost complete
regression after one month.
After 60 days from the beginning of the corticosteroid
therapy the blood analysis showed a normalization of the
levels of C protein and a p-ANCA decrease; the values of
beta 2 microglobulin remained steady.
After 4 months the storage symptoms reappeared.
The renewal of the storage urinary symptoms led the
patient to assume increasing dosages of Prednisone without any therapeutic results. The patient experienced a
pathological rise of glycemia and arterial pressure and
besides a state of worsening osteoporosis. The patient
went through a very bad quality of life with intervals
between micturitions of about 15-20 minutes and
stopped her public relations. In the hypothesis of an
autoimmune disease of the bladder the patient was submitted to an empiric treatment with Cyclosporin (5-8),
without results.
The patient was offered a cistectomy with a ortotoptic
ileal neobladder. Histopathologic examination of the
specimen confirmed the massive plasmacells infiltration
of the bladder mucosa (Figures 2 and 3).
Figure 2.
Plasma cells predominance of the mucosal infiltrate
is evident (E.E., 200 x).
Figure 3.
Gross appearance of the bladder mucosa.
DISCUSSION
Chronic cystitis with sterile urines in its several anatomopathological kinds (interstitial cystitis, eosinophilic cystitis, cistic cystitis) presents with the same symptoms of
acute bacterial cystitis, but lasting in time: frequency,
urgency, painful micturition, sometimes macrocospic
haematuria, until the clinical manifestation of a pain
pelvic syndrome. The chronic cystitis is an underhand
disturb and it is often hard to accurately diagnose.
The presence of plasma cells in the bladder wall is frequent in chronic interstitial cystitis.
In our case report, the phlogistic infiltration of the bladder wall was characterized by one single cellular member, the plasma cells, for over 90% of the whole population. The discover of a policlonal phenotype for chains
kappa and lamda in the histological examination allowed
to exclude the possibility of a plasmocitoma infiltrating
the bladder. According to our knowledge, in literature
only a single case of plasma cells infiltration of the bladder mucosa has been previously described (1) but the
Authors did not report if corticosteroidal therapy mantained the positive effects with time.
The ANCA are antibodies whose location plays an impor-
Figure 4.
The urothelium is denuded and lamina propria
is extensively infiltrated by plasma cells.
The phlogistic infiltration of the bladder wall was
characterized by one single cellular member, the plasma
cells, for over 90% of the whole population (E.E., 200 x).
Archivio Italiano di Urologia e Andrologia 2010; 82, 2
123
M. Pacella , V. Varca, F. Venzanoa, C. Toncini, G. Carmignani, A. Simonato
tant diagnostic role in some sistemic vasculitises. An
increased level of beta 2 microglobulin seems to be less relevant. Beta 2 microglobulin is one small molecule present
in the serum, in the urines and in the cerebrospinal liquid.
It is made of the antigens of HLA and it is present in high
concentration on the surface of some cells of the immune
system. Although it is also used as a marker for some
tumours, it is worth to remember that increased values
are not a clear evidence of neoplasia. In fact, its concentration may increase in a wide range of affections, among
which the autoimmune sistemic diseases.
During the period of action of the corticosteroidal therapy,
besides a meaningful regression of the urinary symptoms,
we noticed the improvement of the cystoscopic features
state and the reduction of the levels of p-ANCA. All these
elements could hint at a chronic cystitis due to autoimmune aetiology, even if we haven’t been technically able to
characterize specific antibodies anti-bladder mucosa.
In addition, a very recent study (9) explored the specific
autoimmune mechanism of urinary bladder developing a
new animal model. Using a novel line of transgenic mice,
Wujiang et al. were the first to demonstrate that the bladder epithelium actively presents self-Ag to the immune
system and induces autoimmune response.
Therefore, it is likely that the cystitis with plasmocells infiltration is less rare than one can think when basing on the
only two reported cases in literature: the spreading of the
clinical practise of systematic cold cup histologic mapping
of bladders with chronical cystitis could reveal a greater
number of cases suffering from this clinical entity. From a
therapeutic point of view, an extended treatment with corticosteroids seems not feasible for the side effects and the
transient state of the benefits. The therapy with
Cyclosporin could turn out effective, even if in our case it
Correspondence
Alchiede Simonato
Ospedale San Martino
Clinica Urologica “L. Giuliani”, pad. 12
Università degli Studi di Genova
L.go Rosanna Benzi, 12 - 16132 Genova, Italy
[email protected]
Virginia Varca, MD
Ospedale San Martino
Clinica Urologica “L. Giuliani”, pad. 12
Università degli Studi di Genova
L.go Rosanna Benzi, 12 - 16132 Genova, Italy
Fabio Venzano, MD
Ospedale San Martino
Clinica Urologica “L. Giuliani”, pad. 12
Università degli Studi di Genova
L.go Rosanna Benzi, 12 - 16132 Genova, Italy
Carlo Toncini, MD
Ospedale San Martino - Anatomia Patologica
L.go Rosanna Benzi, 12 - 16132 Genova, Italy
Giorgio Carmignani, MD
Ospedale San Martino
Clinica Urologica “L. Giuliani”, pad. 12
Università degli Studi di Genova
L.go Rosanna Benzi, 12 - 16132 Genova, Italy
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Archivio Italiano di Urologia e Andrologia 2010; 82, 2
has not been possible to determine because of patient’s
refusal. Despite a total cystectomy with urinary diversion is
an aggressive therapeutic option, it has undoubtly solved
the symptoms of our patient who has regained a good
quality of life and up to now she is greatly satisfied of her
choice.
REFERENCES
1. Thaxton CS, Eggener SE, Schaeffer AJ. Plasma cell infiltration of
the urinary bladder. Urology 2004; 64:156-7.
2. Phatak S, Foster HE Jr. The management of interstitial cystitis: an
update. Nat Clin Pract Urol 2006; 3:45-53.
3. Parsons M, Toozs-Hobson P, J Br. The investigation and management of interstitial cystitis. J Menopause Soc 2005; 11:132-9.
4. Soucy F, Gregoire M. Efficacy of prednisone for severe refractory
ulcerative interstitial cystitis. J Urol 2005; 173:841-3.
5. Sairanen J, Tammela TL, Leppilahti M, Multanen M, Paananan
I, Lehtoranta K, Ruutu M. Cyclosporine A and pentosan polysulfate
sodium for the treatment of interstitial cystitis: a randomized comparative study. J Urol 2005; 174:2235-8.
6. A. Sairanen J, Forsell T, Ruutu M. Long-term outcome of patients
with interstitial cystitis treated with low dose cyclosporine. J Urol
2004; 171:2138-41.
7. Forsell T, Ruutu M, Isoniemi H, Ahonen J, Alfthan O. Cyclosporine
in severe interstitial cystitis. J Urol 1996; 155:1591-3.
8. Pomeranz A, Eliakim A, Uziel Y, Gottesman G, Rathaus V, Zehavi
T, Wolach B. Eosinophilic cystitis in a 4-year-old boy: successful
long-term treatment with cyclosporin Pediatrics 2001; 108:E113.
9. Liu W, Evanoff DP, Chen X, Luo Y. Urinary bladder epithelium
antigen induces CD8+ T cell tolerance, activation, and autoimmune
response. J Immunol 2007; 178:539-46.
ORIGINAL PAPER
Lidocaine spray administration during transrectal
ultrasound guided prostate biopsy modified
the discomfort and pain of the procedure:
Results of a randomized clinical trial.
Lucio Dell’Atti, Carlo Daniele
Urology Unit, Arcispedale “S. Anna”, Ferrara, Italy
Summary
Objectives: We report the results of a study about the possible benefit of lidocaine
spray perineal administration before transrectal ultrasound guided biopsy of the
prostate. Many patients frequently report some kind of discomfort and (or) pain during this procedure, that when pain is severe, may be necessary to interrupt.
Materials and Methods: Between September 2007 and October 2009 372 consecutive
male patients with elevate PSA and (or) abnormal digital rectal and (or) suspect TRUS were
scheduled for prostate biopsy and divided in 3 groups. Group 1 (n = 98) underwent intrarectal
instillation of a lidocaine/prilocaine cream (EMLA R), Group 2 (n = 126) of a 2,5% lidocaine
gel, and Group 3 (n = 148) administration of a lidocaine spray (10 gr/100 ml) before the procedure. A verbal numerical pain score (VNS) from = 0 no discomfort to 10 = severe pain was
admnistrated to the biopsied patients who were asked to evaluate separately the degree of pain
associated with the insertion of the probe and the manoeuvres associated with it and the degree
of pain associated with the biopsy.
Results: The mean value of pain VNS in patients of the first group was respectively 5.3 (2-8)
for the insertion of the probe (first question) and 3.2 (2-7) for the biopsy by itself (second question), whereas in the second group it was 6.2 (4-9) and 3.8 (3-8), and in the third group 3.1 (16) and 2.8 (0-6).
Conclusions: Pain score results showed that the use of intrarectal lidocaine spray provided significantly better pain control than cream and anaesthetic gel. Our pain score data suggests that
lidocaine spray provides efficient patient comfort during prostate biopsy by reducing pain both
during probe insertion and insertion of the needle through the prostate gland.
The use of lidocaine spray makes an excellent alternative, causing a reduction of anal sphincter tone with better patient compliance and tolerability to the ultrasound probe during biopsies
with an optimization in terms of cost-effectiveness of the procedure.
KEY WORDS: Prostate biopsy; Local anesthetic; Prostate innervation.
Submitted 26 January 2010; Accepted 30 April 2010
INTRODUCTION
Over the past twenty years, transrectal ultrasound has
greatly simplified the procedure of prostate biopsy (BP),
while increasing its accuracy and sensitivity. Transrectal
ultrasound guided BP is now a routine outpatient procedure that is easy to learn and quick and simple to perform,
but still associated to side effects including pain and discomfort.
Over 70% of patients feel pain and discomfort during the
procedure that makes it difficult to continue and sometimes cause to stop procedure (1).
BP is today the only mean of obtaining an early diagnosis
of prostate cancer in order to cure the disease. The efficacy of this procedure is dependent on the number of cores
obtained, hence the need to make it as comfortable as possible for the patient, mantaining it outpatient and low cost.
The pain associated with BP originates mainly in the
pseudo-capsule or stroma of the peripheral zone that is
richly innervated by fibers from the S2-S5 spinal cord and
from the ortho-sympathetic chain, through the posterolateral neuro-vascular pedicles.
On the contrary, the anterior fibro-muscular prostate, is
not significantly innervated (2, 3).
Archivio Italiano di Urologia e Andrologia 2010; 82, 1
125
L. Dell’Atti, C. Daniele
Currently, the techniques most frequently proposed for
local anesthesia during transrectal BP appear to be the
local application of anesthetic gel and the periprostatic
injection of lidocaine (4).
The rationale for the use of intrarectal application of
anesthetic gel is related to the high capacity of absorption
of drugs through the rectal mucosa and the presence of a
rich innervation of the prostate in the space between rectum and prostate.
Periprostatic infiltration of anesthetic before BP may be
directed to the space between prostate and seminal vescicles or at the prostatic apex (5).
The optimal schedule of injections is difficult to define
such as the ideal dose of anesthetic to be injected,
although the vast majority of authors use 5 or 10 ml of
lidocaine (5, 6).
In our view, an important factor of the state of discomfort during the procedure is the tone of the anal sphincter and the presence of the ultrasound probe that
increases pressure and causes stretching of muscle fibers
and sensory nerve fibers.
The pain caused by biopsy itself contributes less significantly to the state of discomfort of the patient.
The presence of anal stenosis, haemorrhoidal prolapse or
anal fissures increases the discomfort of the procedure.
In this study we aimed to assess the efficacy of a new
method of application of local anesthetic during
prostate biopsy using lidocaine spray in comparison
with customary method with intrarectal lidocaine gel
and lidocaine/prilocaine (EMLA R) anesthetic cream
(7, 9, 15).
MATERIAL
AND METHODS
The criteria for prostate biopsy and patient enrolment in
the study were:
– abnormal digital rectal examination;
– PSA > 4ng/ml;
– significant increase of PSA over time (PSA velocity > 0.75 ng/ml/year);
– PSA 2-4 ng/ml (patients with family history of prostate
cancer and PSA ratio < 10%);
– hypoechoic lesions at prostatic transrectal ultrasound
(TRUS);
Were excluded from the study patients with:
– PSA > 100 ng/ml with suspect digital rectal examination;
– radiological or scintigraphic evidence of metastases;
– positive histology after TURP;
– reduced life expectancy;
– concomitant severe pathologies.
Between September ’07 and October ’09 we selected 372
patients undergoing transrectal ultrasound guided
prostate biopsy. For this procedure a G.E. ultrasound
(LOGIQ 7) with “end-fire” multi-frequency convex
probe and 18 Gauge tru-cut needle were used.
Biopsies were performed alternately by two operators
with experience Rectal enema and antibiotic prophylaxis
were administered to prevent infectious sequelae (11,
12) and patients were asked to empty the bladder prior
to the procedure, because in our opinion the bladder
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Archivio Italiano di Urologia e Andrologia 2010; 82, 1
repletion is an important element of discomfort during
BP. Before the application of anesthetic a thorough disinfection of the skin of the perineum was carried out with
the use of common solutions of povidone iodine or
chlorexidine (10, 11).
The patients were divided into 3 groups.
Group 1 (n = 98) underwent intrarectal instillation of
a 25 mg lidocaine/ 25 mg prilocaine cream (EMLA R)
applied 5 minutes before the procedure, Group 2 (n =
126) was treated with 2,5% lidocaine gel applied 5 minutes before the procedure, and Group 3 (n = 148) was
treated with the administration of a lidocaine spray
(10gr/100ml) applied 2 minutes before the BP.
The first intention was to obtain 14 TRUS-guided cores
in all the patients.
Pain was self evaluated by the patiens with the use of a
simple rating scale of pain called Verbal Numerical Scale
(VNS). This is a scale easily understood by the patient
who chooses a number between 0 (no pain) to 10 (the
greatest pain imaginable) to represent the level of pain.
Immediately after the end of the procedure two scales
VNS of pain were separately administered to measure the
pain due to the insertion of the ultrasound probe and its
movement during the procedure and the pain caused by
biopsy itself.
RESULTS
Only in 4 patiens we were unable to insert TRUS probe
for the presence of fibrous anal in 3 and for severe haemorrhoidal prolapse in another.
The mean age of patients in the group treated with
EMLA cream was 67 years (range 52-75), the value of
the PSA 8.2 (range 4.5-12.2), total prostate volume 54
ml (36-102).
In the second group treated with use of 2.5% lidocaine gel
the mean age was of 70 years (range 53-76), the value of
the PSA 7.1 (range 2.5-14.2), total prostate volume 49 ml
(range 32-120).
In the third group treated with use of lidocaine spray 10
gr/10 ml the mean age was 69 years (range 48-74), the
value of the PSA was 9.2 (range 3.6-17.2), total prostate
volume 56 ml (range 28-96).
We performed a mean of 11.2 (range 7-16), 10.8 (range
5-14), 12.4 (range 6-16) biopsies, respectively for first,
second and third group.
The mean pain in the visual numerical scales in patients
in the first group was respectively 5.3 (2-8) in the first
questionnaire and 3.2 (2-7) in the second questionnaire,
in the second group was of 6.2 (4-9) and 3.8 (3-8), in the
third group was of 3.1 (1-6) and 2.8 (0-6).
A statistically significant difference was observed in the
tolerability of the procedure according to the first questionnaire, not to the second questionnaire (p < 0.001).
Subjects aged > 70 years in all three groups of patients
tolerated the procedure better according to both questionnaires (average pain VNS was respectively 2.8 and
1.9).
In the elderly there is a reduced perception of pain that
can be related to several factors such as the decrease in
the number of nociceptors and nociceptive afferents
responsible for the threshold and tolerance of pain (8).
Lidocaine spray administration during transrectal ultrasound guided prostate biopsy modified the discomfort and pain of procedure
DISCUSSION
Our study reveals that the use of lidocaine spray in the
procedure of transrectal BP is a technique easier, cheaper and more effective than the traditional use of the anesthetic gel and the anesthetic cream EMLA.
Currently, the techniques most frequently proposed for
local anesthesia during transrectal BP appear to be the
application of gel or an injection of lidocaine around the
prostate.
Since our study suggests that the main element of discomfort for the patient during the procedure results from the
introduction of the ultrasound probe and its movements
during the procedure than by the biopsy itself, we discarded the option of periprostatic injection of anesthetic.
This new technique of anesthetic application by lidocaine spray proved to be an excellent alternative to those
currently practiced by most urologists, owing to the
reduction of the anal sphincter tone with better patient
compliance and tolerability to the ultrasound probe during the procedure and with optimization in terms of
cost-effectiveness of the procedure.
A single spray dispenser of lidocaine (10 gr/100 ml)
allows to handle a number of patients equal to that treated wth a double pack of 2.5% lidocaine gel and five
times more than using a single pack of prilocaine/lidocaine cream.
Furthermore spray anesthetic administration reduces the
time of the procedure of 2-5 minutes in comparison to
the other two methods.
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1. Buckler MR, Bryant NJ, Tiwari P, et al. Tolerance of local anesthetic for transrectal ultrasound-guided prostate biopsy: our experience
and a literature review. Can Assoc Radiol J 2006; 57:169-74.
2. Mottet N, Costa P, Bali JP. Autonomic nervous system and prostatic physiology. Specific features of the alpha-adrenergic system. Prog
Urol 1999; 9:26-36.
3. McVary KT, McKenna KE, Lee C. Prostate innervation. Prostate
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4. Bingqian L, Peihuan L, Yudong W, et al. Intraprostatic local anesthesia with periprostatic nerve block for transrectal ultrasound guided prostate biopsy. J Urol 2009; 182:479-83.
5. Rodriguez A, Kyriakou G, Leray E, et al. Prospective study comparing two methods of anesthesia for prostate biopsies: apex periprostatic nerve block versus intrarectal lidocaine gel: review of literature. Eur Urol 2003; 44:195-200.
6. Ozveri H, Cevik I, Dillioglugil O, Akdas A. Transrectal periprostatic lidocaine injection anesthesia for transrectal prostate biopsy: a
prospective study. Prostate Cancer Prostatic Ds 2003; 6:311-4.
7. Galosi AB, Minardi D, Dell’Atti L, et al. Tolerability of prostate
transrectal biopsies using gel and local anesthetics: results of a randomized clinical trial. J Endourol 2005; 19:738-43.
8. Rodrigues AO, Machado MT, Wroclawski ER. Prostate innervation and local anesthesia in prostate procedures. Rev. Hosp. Clin.
Fac. Med. Sao Paulo 2003; 57:287-92.
9. Hergan L, Kashefi C, Parsons JK. Local anesthetic reduces pain
associated with transrectal ultrasound-guided prostate biopsy: a
meta-analysis. Urology 2007; 69:520-5.
10. Rees M, Ashby EC, Pocock RD, et al. Povidone-iodine antisepsis
for transrectal prostatic biopsy. Br Med J 1980; 281:650.
11. Lindert KA, Kabalin JN, Terris MK. Bacteriemia and bacteriuria
after transrectal ultrasound guided prostate biopsy. J Urol 2000;
164:76-80.
12. Aron M, Rajeev TP, Gupta NP. Antibiotic prophylaxis for transrectal needle biopsy of the prostate: a randomized controlled study.
BJU Int 2000; 85:682-685.
13. Seymour H, Perry MJ, Lee-Elliot C, et al. Pain after transrectal
ultrasonography-guided prostate biopsy: the advantages of periprostatic local anaesthesia. BJU Int 2001; 88:540-544.
14. Montoliu Garcia A, Juan Escudero J, Ramos de Campos M, et al.
Prospective randomized study on the use of lidocaine local anesthesia in prostate biopsy. Arch Esp Urol 2009; 62:339-47.
15. Yurdakul T, Taspinar B, Kilic O, et al.Topical and long-acting
local anesthetic for prostate biopsy: a prospective randomized placebo-controlled study. Urol Int 2009; 83:151-4.
Correspondence
Lucio Dell’Atti, MD
Via Goretti, 13 - 44123 Ferrara, Italy
[email protected]
Carlo Daniele, MD
Urology Unit - Arcispedale “S. Anna”
44123 Ferrara, Italy
[email protected]
Archivio Italiano di Urologia e Andrologia 2010; 82, 1
127
ORIGINAL PAPER
Extracorporeal shock wave therapy in the treatment
of Peyronie’s disease: Long term results.
Gian Maria Busetto
Policlinico Umberto I, Dipartimento Urologia "U. Bracci", Sapienza Università di Roma, Italy
Summary
Purpose: Controversial data on ESWT (Extracorporeal Shock Wave Therapy) for the
treatment of Peyronie’s disease are controversial. This study was performed to access
the efficacy, reliability and the side-effects of the ESWT.
Materials and Methods: From 2000 to 2004, 157 patients with an average age of 58
years and with Peyronie’s disease were enrolled for a conservative treatment. All 150
eligible patients were treated with ESWT, using Dornier Compact Delta II UIMS® lithotripter.
The median number of treatments per patient was 3.5 with the delivery of 2000 shock waves
(SW) for each treatment. There was no use of anaesthesia and analgesy. An ultrasound study
was made for each patient before treatment. We considered: plaque size, penis curvature, pain,
penis rigidity and tumescence, sexual intercourse ability and side-effects. Median follow-up of
the study was 36.9 months.
Results: Average duration of the treatment was 20 minutes without relevant side-effects. With
reference to the curvature, we obtained a significative reduction in 33.3% of the patients, whereas the plaque size was not statistically reduced. Regarding the pain issue we achieved good
results with a reduction in more than 90% of the patients and a complete relief in 6%. The quality of the intercourse was reported slightly enhanced. No significant difference was observed in
penis tumescence and rigidity.
Conclusions: ESWT is a non-invasive treatment for the Peyronie’s disease. Our study confirms
that the best results are obtained regarding pain and less with the curvature. For the plaque
size and quality of sexual intercourse the results are not satisfactory.
KEY WORDS: ESWT (Extracorporeal Shock Wave Therapy); Peyronie’s disease; Penile recurvatum.
Received 29 January 2010; Accepted 30 March 2010
INTRODUCTION
Peyronie’s disease is a connective tissue disorder and is
also the most frequent cause of penile curvature, a distressing and sexually disabling disease; it tipically regards
middle aged men. The tunica albuginea and the erectile
tissue, that is adjacent, are affected by localized plaques.
Early inflammatory stages show thickening of the tunica,
while later on fibrotic, often calcified plaque is typical (1).
Two phases are usually reported, one acute and one chronic. The acute phase involves an inflammation that can lead
to pain experienced from the patient either in the soft
(flaccid) state or during erection. The chronic phase is
when the scar develops and penile deformity occurs, pain
during this phase is usually limited to the erect state and
doesn’t respond to pharmacological treatments. In many
cases, the pain will gradually settle down and disappear
without treatment in a few months, but the bend in the
penis may remain a problem, making sexual intercourse
128
Archivio Italiano di Urologia e Andrologia 2010; 82, 2
difficult. The predominantly dorsal deviation that is the
main symptom can be combined with erectile dysfunction
(2). The etiophathology of the disease remains unclear and
a study has suggested a prevalence rate as high as 8.9%
(3). Despite the innovative investigations in cell culture
with identification of potential biomarkers (4), no causal
therapy is yet available. Surgical procedures that are the
standard choice of treatment in cases of severe sympomatic angulation (5, 6), include: plication procedures (attempt
to straighten the penis by trying to shorten the longer side
to match the shorter side), excision-grafting procedures
(incision of the scar in the tunica albuginea and straightening of the penis followed by reconstruction of the resultant defect using a variety of graft material like vein, buccal
mucosa, preputial skin, pericardial sac, small intestinal
submucosa). However, these procedures have significant
risks, such as penile shortening, reduced sensation, impo-
Extracorporeal shock wave therapy in the treatment of Peyronie’s disease: Long term results
Table 1.
tence, new fibrotic reaction (7). There is no clear
Patients characteristic.
indication as to when semi-invasive and surgical
procedures have to be initiated. It seems to be
generally accepted that conservative therapy is
Patients, n
150
required in the earlier inflammatory, painful
58
(24-84)
Average age, years
stages (8). A wide range of conservative therapies
Duration of disease, months
3.3
(1-6)
have been proposed, including radiation, oral
Average plaque size, mm2
299.9
(50-508)
drugs such as Potaba, tamoxifen, colchicine and
vitamin E and intralesional injections of veraCalcification
60/150
(40%)
pamil and interferon. Extracorporeal shock wave
Patients with deviation
150/150 (100%)
therapy (ESWT) has been used since the 1980s
Average
deviation,
degree
49.9
(15-88)
and was introduced by Bellorofonte and associSuffering pain
78/150
(52%)
ates (9) as a conservative option. The action
mechanism of ESWT is unclear, although an
Quality of sexual intercourse
Table 3
improvement in vascularization with consecutive
resorption of calcification has been discussed as
one possible mechanism (10). Another possible
give informed consent for the study. The majority of
action could be the creation of contralateral scarring of the
patients who gave the consent desired to avoid the surpenis resulting in “false” straightening (11). In connection
gical invasive procedures.
to non-calcified diseases, a change in the milieu of the free
radicals or a direct disturbance of the pain receptors could
ESWT technique.
be a reason for the pain-relieving effect (12, 13). There are
ESWT was performed with an ultrasound guidance
many studies regarding the Peyronie’s disease treatment
using a Dornier Compact Delta II UIMS® lithotripter
with ESWT (14, 21-26) (Table 5), and the authors report
(Dornier MedTec Europe GmbH, Wessling Germany) delivan improvement in symptoms of pain, deviation and sexering 2000 shock waves per treatment session, with an
ual intercourse; the studies are different for the type of
emission frequency of 120 shocks/min.
lithotripter, number of settings, number of impulses and
ESWT was started with a low energy flow density and
the energy rate thus demonstrating that ESWT is still not
the power was increased step by step according to the
standardized and must be considered as an interesting, but
patient tolerance level, usually up to 0.16 mJ/mm2. Even
clinically experimental, form of therapy (14).
if the majority of the studies used 3000 SW for each
We evaluated, as objective of our study, changes in
application, we used a scheme of 2000 SW because in
plaque size, pain relief, enhancement of curvature of the
our initial experience, applying more shock-waves, we
penis, restoration of normal sexual function, penis rigidhave had more side-effects presented by severe urethral
ity and tumescence and side-effects.
bleeding and extended skin haematoma.
Initially we treated 20 patients with 3000 SW and everyMATERIAL AND METHODS
one, eveyone presented skin haematoma and in 12 it was
Patients. From January 2000 to September 2004 157
extended. In 9 patients we observed also urethral bleedpatients with Peyronie’s disease and with an average age
ing.
of 58 years (range 24-84 years), were treated by ESWT
The average duration of the treatment was 20 minutes. If
improvement in symptoms but no complete straightenand were enlisted for a prospective design study. All the
patients’ characteristics are
listed in Table 1. Of 150 eliTable 2.
gible patients for the study,
Plaque size and deviation before and after ESWT.
all with a plaque (calcified
or not) and the deviation of
Before treatment
After treatment
p value
the penis, none was given
2
Plaque size, mm
299.9 (50-508)
295.0 (10-555)
0.0854
any adjuvant oral therapy,
Curvature,
degree
49.9
(15-88)
25.2
(9.6-40.8)
0.044
before and after the treatment, nor phosphodiesterase
type 5 inhibitor and prostaTable 3.
glandine E1.
Before and after ESWT.
We obtained from each
patient a signed consent form
Sexual intercourse
Sexual intercourse
and all patients were
before treatment
after treatment
informed with all the details
about the therapeutic options
Possible
15
(10%)
36
(24%)
for the disease, furthermore
Moderately restricted
103
(68.6%)
94
(62.6%)
we asked every one a detailed
Severely
restricted
24
(16%)
12
(8%)
sexual and medical detailed
Impossible
8
(5.3%)
8
(5.3%)
history. Of the initial group of
157 patients, 7 refused to
Archivio Italiano di Urologia e Andrologia 2010; 82, 2
129
G.M. Busetto
Table 4.
Side effects.
Side
150
33
30
3
69
6
Patients, n
Total side-effects
Superficial skin haematoma
Urethral bleeding
Moderate local pain during treat.
Strong local pain during treat.
effects
(22%)
(20%)
(2%)
(43%)
(4%)
ing was obtained and also if no effect was seen, the treatment was repeated after 2 months. The treatment was
halted to those patients that suffered strong pain during
treatment and no more treatments were performed to
those reporting side-effects like penis skin haematoma
and urethral bleeding. The median number of treatment
per patient was 3.5 (range 1-9). We didn’t use any kind
of anaesthesia and analgesia. Patients were arranged in a
reclining position with a supportive stand to stabilize the
penis and avoid injury to the testes. To obtain a precision
delivery of the shock waves we localized the plaque
using a 7.5-MHz inline linear ultrasound transducer. The
ultrasound drill permitted also the evaluation of the calcification of the plaque, as an hyperechogenic image.
The median follow-up of the study was 36.9 months
(range 33-41 months).
Standardized diagnostic evaluation.
The basal data before treatment of all patients are given
in table 1.
The plaque size was obtained as a product of length and
width using for the measurement a measuring tape and
was evaluated before and after treatment. The curvature
(degree), calculated before and after treatment, was measured using a goniometer and by photo documentation
after artificial induction of erection using a vacuum device.
Pain during erection was, instead, evaluated using a visual analog scale (VAS 0-5). Finally we asked all the patients
a personal feedback regarding the frequency, the quality
and the duration of the erection according to the Bahren
and Stief (15) score system: E1 little tumescence, no rigidity, E2 moderate tumescence, no rigidity, E3 full tumes-
cence, no rigidity, E4 full tumescence, moderate rigidity,
E5 full tumescence, full rigidity. The quality of intercourses was evaluated using a score system by asking all
patients if the coitus was possible, moderately restricted,
severely restricted or impossible. The questionnaire was
based on three main parameters that describe sexual intercourses difficulty: rigidity deficit, altered penile curvature
and pain.
We finally evaluated the complication following the
treatment.
Statistical analyses.
Statistical analyses were performed using a GraphPad
InStant system, version 3.05 (San Diego, CA USA). P values were calculated and were considered significant with
a p < 0.05.
RESULTS
Side-effects. We didn’t observe any relevant side effect
during and after ESWT treatment. Of 150 evaluable
patients only 33 (22%) reported side effects. In particular 30 (20%) had a superficial skin haematoma and 3
(2%) had a slight urethral bleeding. We also reported 69
(43%) patients with moderate local pain during the treatment and 6 (4%) with a strong pain during treatment.
None of the patients reported a urethral stricture during
our follow-up of 36.9 months (Table 4).
Plaque size. With the ESWT treatment we didn’t observe
a significant reduction in plaque size. In fact in 30
patients (20%) we observed a size reduction of the
plaque, in 36 patients (24%) we saw a size increase of the
plaque and in 84 (58%) there were no changes in the
plaque size (p = 0.0854). All the characteristics regarding
the plaque are listed in Table 2.
Regarding the 60 patients with the calcified plaque in 6
(10%) of them there were no longer ultrasound evidence
of the calcification. In only 1 patient (0.75%) with a noncalcified plaque we saw a new calcification.
Curvature. Generally, the curvature did not change as we
expected. Of the 150 patients 50 (33.3%) had a reduction of the curvature with a mean reduction of 25.2
degrees (+/-15.6 degrees) (p = 0.044), 96 (64%) had no
enhancement of the curvature and 4 (2,66%) had an
increase of the curvature with a mean increase of 12
degrees (7-17 degrees) (Table 2).
Table 5.
Results of previous studies of ESWT for Peyronie’s disease (27).
130
References
No.
pts.
Mean
follow up
(mo.)
Abdel-Salam et al. (21)
24
3-9
14 (58)
14/24 (58)
17/24 (72)
14/24 (58)
Hamm et al. (22)
28
not avail.
not avail.
18/28 (64)
13/16 (81)
20/28 (71)
Hauck et al. (14)
20
9 (3-13)
2
(10)
10/20 (50)
5/9
3/20
Husain et al. (23)
34
8 (5-11)
not avail.
15/32 (47)
12/20 (60)
Kiyota et al. (24)
4
<1
1
0/4
Manikandan et al. (25)
42
6 (2-18)
not avail.
22/38 (58)
21/25 (84)
5/42
(12)
Mirone et al. (26)
21
not avail.
11 (52)
11/14 (75)
16/21 (76)
9/12
(75)
Archivio Italiano di Urologia e Andrologia 2010; 82, 2
No. decrease
plaque
size (%)
(25)
No. decrease
penile
curv. (%)
(0)
No. decrease
pain (%)
4/4
(56)
(100)
No. improve
sexual
intercourse(%)
(15)
not avail.
not avail.
Extracorporeal shock wave therapy in the treatment of Peyronie’s disease: Long term results
Pain. With pain we obtained good results. Of the 150
patients 78 (52%) suffered pain. Of this 78 patients more
than 90% reported good improvement in the sintomatology (p < 0.01); 9 (6%) of them reported a complete pain
relief.
Sexual function. After ESWT treatment the quality of the
intercourses are reported slightly enhanced. We didn’t prescribe any PDE5 inhibitors or PGE1 drugs to avoid altered
outcomes of the study. We observed also some cases of
worsened sexual intercourses. Table 3 shows the detailed
change in sexual activity before and after the treatment.
Penis tumescence and rigidity. No significant difference was
observed before and after the treatment (average score
before treatment 4.5 and average score after treatment
4.4), only 23 patients (15.3%) reported a difference.
DISCUSSION
Peyronie’s disease is a connective tissue disorder involving the growth of fibrous plaques in the soft tissue of the
penis.
Specifically the process occurs in the tunica albuginea, a
fibrous envelope surrounding the penile corpora cavernosa, causing an abnormal curvature of the penis (16).
While the scar in the tunica albuginea is undergoing the
process of remodelling, penile distortion may increase,
remain static or resolve and disappear in younger spontaneously. In most patients the curvature remains static
as the scar matures, although, in some patients, it
becomes worse as fibrosis ensues and the scar contracts
(17). In 25% of these patients the scarring process progresses to calcification, and in 25% of those it progresses to bone formation (18). We prospectively evaluated
the efficacy of ESWT for Peyronie’s disease in 150
patients. The indication for ESWT in Peyronie’s disease
is debated; it could be used both in non-calcified and
calcified plaque with an important effect on the penis
pain. First of all, before the treatment, we have to establish the goal of the ESWT therapy. The goal should be
the reduction in plaque size with a consecutive reduction in the deviation angle, and a good improvement in
the capacity to have regular sexual intercourse.
Glancing the literature we made a comparison with the
results of our study (Table 5).
Regarding the pain we can say that it is more difficult to
evaluate because is a subjective parameter and it is not
infrequent a spontaneous regression of the pain particularly in early stages (19-20). Spontaneous regression of the
disease has been seen in 13%, stable disease in 47% and
progression in 40% of the cases (20). To treat the pain is
also possible to apply a conservative treatment with analgesics and anti-inflammatory medication; this treatment is
effective in particular in early inflammatory stages because
is mainly is a symptom-directed approach (14), but is less
effective in later stages when the pain is only during erection. With the ESWT it is possible in some cases to obtain
a more lasting analgesia sometimes also in later stages. In
regards to the ESWT mechanism of action it has been suggested an improvement in vascularization with consecutive resorption of calcification (10), as an alternative it has
been proposed, in non-calcified plaques, a possible action
on free radicals or pain receptors (12-13).
As in our patients no particular side-effects were observed
in any study. Main side-effects, moderate and transient,
noticed are the same in all studies and in our series; pain
during treatment, skin haematoma and urethral bleeding
(14, 21-26).
We didn’t report a significant decrease in plaque size
because we observed an overall reduction of the plaque
in only 20% of our patients. We reported also a reduction of the size of the calcified plaques in 10%. In the literature are described reduction in plaque size in respectively 10% (22), 25% (24), 52% (26), and 58% (21). We
remark that in all studies there isn’t any note regarding
the extent of the plaque size decrease nor any hint concerning the distinction between calcified and not calcified plaques.
Concerning the penis curvature we didn’t report an
important reduction, although 33.3% (50) of the
patients had a significant reduction with a mean reduction of 25.2 degrees (+/-15.6 degrees). On the contrary
96 patients (64%) had no enhancement of the curvature
and even more noticeably 4 patients (2,66%) reported a
worsening of the curvature during our long term followup.
Other studies report a curvature reduction from 0% to
75% (14, 21-26). Only one study reports a significant statistical reduction (24). It is debatable if this statistical significant reduction is really of practical value for the
patient. Only one series of the studies that we analysed did
not show any worsening of the curvature (22).
Of 150 patients who signed up in our study 22 (14.6%)
underwent surgery later, ESWT therapy not affecting in
any way the surgical procedures. Other patients agreed
with the simple conservative ESWT approach hoping to
achieve an improvement in symptoms and pain without
any invasive procedures. We can confirm that for curvature
less than 30 degrees surgery seems not to be indicated.
The pain is the parameter that is more improved with
more than 90% of the 78 patients suffering pain reporting
good improvement of the sintomatology and 9 (6%) of
them reporting a complete pain relief. In literature are also
reported good improvements in pain: one study, but with
only 4 patients, refers 100% of improving (24); others
report respectively 56% (14), 60% (23), 72% (21), 76%
(26), 81% (22), and 84% (25). What we can notice is that
pain seems to decrease more rapidly with ESWT treatment
than without any treatment. However we should still
establish if the pain hault because of the treatment or
because in the majority of the affected people the painful
sintomatology resolves spontaneously with time (20).
Another important aspect is the sexual function. This
parameter is very difficult to evaluate because there are
many different way to measure it and because it is a subjective symptom. The problem is to evaluate this data
without objective measurement of the quality of sexual
intercourse. Anyhow 5 of the analyzed studies show an
improvement of this aspect ranging from 12% to 75% (14,
21, 22, 25, 26).
Other 2 studies don’t include a sexual evaluation (23-24).
Clear data on changes in tumescence and rigidity are missing in all analyzed series. In our study there is an enhancement of sexual intercourse, in particular patients who
referred a severe sexual dysfunction reported in many
Archivio Italiano di Urologia e Andrologia 2010; 82, 2
131
G.M. Busetto
cases an improvement such as those who referred a moderate dysfunction. Patients that referred to have impossible
sexual intercourse remained unchanged. Regarding penis
tumescence and rigidity only 23 patients (15.3%) reported a slight improvement although this data is purely subjective and not validated.
After analyzing all the outcomes of different studies it is
important to observe that everyone used a different
lithotripter with different modalities of application.
Our scheme was based on the administration of 2000
shock waves for treatment with an average number of
treatment of 3.5, in other studies the number of shock
wave for treatment ranges from 1000 to 4000 and the
number of treatments from 1 to 5 per patient. All the
series used a different energy (14, 21-26).
Furthermore we must acknowledge that different
patients with also subjective evaluations results in different outcomes. Therefore, due to different technical
aspects in different patient groups it is difficult to define
the more appropriate protocol of ESWT for this specific
disease. In the case calcified plaque ESWT could be the
first approach for patients refusing an invasive approach
such as surgery. Noncalcified plaques could be treated
with ESWT after the drugs failure.
CONCLUSIONS
Our study is relevant due to the high number of patients
involved (the highest reported to date) and to the long
follow-up (36.9 months).
In consideration to the results obtained we can outline
some important conclusion in relation to the modality of
application of ESWT in Peyronie’s disease:
Plaque size reduction. There is no significant reduction of
the plaque size since it was reported in only 20% of
patients and in only 10% of those with a calcified
plaque.
Pain. In 90% of the patients there is a pain improvement
although we are not able to differentiate if this result
depend on the treatment because in the initial acute
phase of the disease pain can dissolve by itself or be easily controlled with oral analgesics.
Curvature. A statistically significant reduction of the
penis curvature was reported with a median improvement of 25.2 degrees.
Sexual function. A slight improvement of sexual function
can be certainly ascribed to the reduction in penis curvature and penis pain.
Penis tumescence and rigidity. There is no significative
difference between tumescence and rigidity before and
after the treatment.
In conclusion the results obtained with the ESWT, a noevidence based therapy, for the treatment of Peyronies’s
disease are not fully satisfactory.
The best outcomes have been achieved in the reduction
of penis curvature and penis pain (both flaccid and rigid
condition).
In our opinion ESWT should be proposed as a possible
conservative treatment to those selected patients that
refuse any surgery invasive approach.
Our schedule of procedure is safe and without relevant
side-effects, therefore we believe that is certainly the
132
Archivio Italiano di Urologia e Andrologia 2010; 82, 2
most appropiate since others didn’t reported better
results. Owing to the high number of patients, the long
follow-up, the high number of parameters evaluated the
present study set up, at the moment, an important clinical evidence.
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suffering from induratio penis plastica. Eur Urol 1999; 36:327330.
27. Hauck EW, Hauptmann A, Bschleiper T, et al. Questionable efficacy of extracorporeal shock wave therapy for Peyronie’s disease:
results of a prospective approach. J Urol 2004; 171:296-299.
Correspondence
Gian Maria Busetto, MD
Dipartimento Urologia "U. Bracci"
Università della Sapienza
Policlinico Umberto I, Roma, Italy
Archivio Italiano di Urologia e Andrologia 2010; 82, 2
133
INSTRUCTIONS TO AUTHORS
AUTHORS’ RESPONSIBILITIES
Manuscripts are accepted with the understanding that they have not
been published or submitted for publication in any other journal.
Authors must submit the results of clinical and experimental studies
conducted according to the Helsinki Declaration on clinical research
and to the Ethical Code on animal research set forth by WHO (WHO
Chronicle 1985; 39:51).
The Authors must obtain permission to reproduce figures, tables and
text from previously published material.
Written permission must be obtained from the original copyright
holder (generally the Publisher).
MANUSCRIPT PRESENTATION
Authors must submit the text (MAC and WINDOWS Microsoft Word
are accepted) and illustrations by e-mail.
As an alternative manuscripts can be submitted by surface mail on
disk with two hard copies of the manuscript and two sets of illustrations.
Manuscripts must be written in English language in accordance
with the “Uniform Requirements for Manuscripts submitted to biomedical
journals” defined by The International Committee of Medical Journal
Editors (http://www.ICMJE.org). Manuscripts in Italian language can
be published after translation (expenses will be charged to the
Authors). Manuscripts should be typed double spaced with wide
margins.
They must be subdivided into the following sections:
TITLE PAGE
It must contain:
a) title;
b) a short (no more than 40 characters) running head title;
c) first, middle and last name of each Author without abbreviations;
d) University or Hospital, and Department of each Author;
e) last name, address and e-mail of all the Authors
f) corresponding Author
g) phone and/or fax number to facilitate communication;
h) acknowledgement of financial support;
i) list of abbreviations.
SUMMARY
The Authors must submit a long English summary (300 words, 2000
characters).
Subheadings are needed as follows:
Objective(s), Material and method(s), Result(s), Conclusion(s).
After the summary, three to ten key words must appear, taken from
the standard Index Medicus terminology.
TEXT
For original articles concerning experimental or clinical studies
and case reviews, the following standard scheme must be followed:
Summary – Key Words - Introduction - Material and Methods Results – Discussion - Conclusions - References - Tables - Legends
- Figures.
SIZE OF MANUSCRIPTS
Literature reviews, Editorials and Original articles concerning experimental or clinical studies should not exceed 20 typewritten pages
including figures, tables, and reference list. Case reports and notes on
surgical technique shouid not exceed 10 type written pages (references are to be limited to 12). Letters to the editors should be not
longer than 1000 words.
REFERENCES
The Author is responsible for the accuracy of the references.
References must be sorted in order of quotation and numbered with
arabic digits between parentheses. Only the references quoted in the
text can be listed. Journal titles must be abbreviated as in the Index
Medicus. Only studies published on easily retrieved sources can be
quoted. Unpublished studies cannot be quoted, however articles “in
press” can be listed with the proper indication of the journal title, year
and possibly volume. References
must be listed as follows:
JOURNAL ARTICLES
All Authors if there are six or fewer, otherwise the first three, followed
by “et al.”. Complete names for Work Groups or Committees.
Complete title in the original language.
Title of the journal following Index Medicus rules. Year of publication; Volume number: First page.
Example: Starzl T, Iwatsuki S, Shaw BW, et al. Left hepatic trisegmentectomy Surg Gynecol Obstet 1982; 155:21.
BOOKS
Authors - Complete title in the original language. Edition number (if
later than the first). City of publication: Publisher, Year of publication.
Example: Bergel DIA. Cardiovascular dynamics. 2nd ed. London: Academic Press Inc., 1974.
BOOK
CHAPTERS
Authors of the chapters - Complete chapter title. In: Book Editor,
complete Book Title, Edition number. City of publication:
Publisher, Publication year: first page of chapter in the book.
Example: Sagawa K. The use of central theory and system analysis.
In: Bergel DH (Ed), Cardiovascular dynamics. 2nd ed. London: Academic
Press Inc., 1964; 115.
TABLES
Tables must be aimed to make comprehension of the written text
easier. They must be numbered in Arabic digits and referred to in
the text by progressive numbers. Every table must be accompanied
by a brief title. The meaning of any abbreviations must be
explained at the bottom of the table itself.
(If sent by surface mail tables must be clearly printed with every
table typed on a separate sheet).
FIGURES
(graphics, algorithms, photographs, drawings)
Figures must be numbered and quoted in the text by number.
The meaning of all symbols, abbreviations or letters must be indicated. Histology photograph legends must include the enlargement ratio and the staining method. Legends must be collected in
one or more separate pages.
(If sent by surface mail figures must be submitted in duplicate. On
the back side of each figure the following data must appear: figure
number, title of the paper, name of the first Author, an arrow
pointing to the top of the figure).
Please follow these instructions when preparing files:
• Do not include any illustrations as part of your text file.
• Do not prepare any figures in Word as they are not workable.
• Line illustrations must be submitted at 600 DPI.
• Halftones and color photos should be submitted at a minimum
of 300 DPI.
• Power Point files cannot be uploaded.
• Save art as either TIFF or EPS files.
• If at all possible please avoid transmitting electronic files in JPEG
format. If this is unavoidable please be sure to save the JPEG at
the highest quality available and at the correct resolution for the
type of artwork it is
• Color art must be saved as CYMK, not RGB.
• PDF files for individual figures may be uploaded.
MANUSCRIPT
REVIEW
Only manuscript written according to the above mentioned rules
will be considered. All submitted manuscripts are evaluated by the
Editorial Board and/or by two referees designated by the Editors.
The Authors are informed in a time as short as possible on whether
the paper has been accepted, rejected or if a revision
is deemed necessary.
The Editors reserve the right to make editorial and literary corrections with the goal of making the article clearer or more concise,
without altering its contents. Submission of a manuscript implies
acceptation of all above rules.
PROOFS
Authors are responsible for ensuring that all manuscripts are accurately typed before final submission. Galley proofs will be sent to
the first Author. Proofs should be returned within seven days from
receipt.
REPRINTS
A copy of the issue in which the article appears will be provided
free of charge. Reprints are not provided. The cost to obtain the
PDF file of the article is Euro 50.